WO2025149498A1

WO2025149498A1 - Benzylpiperidine derivatives as trp4 antagonists for the treatment of inflammatory diseases

Info

Publication number: WO2025149498A1
Application number: PCT/EP2025/050285
Authority: WO
Inventors: Susanne Elisabeth Berglund; Peter Robert Hansen; Magnus Nilsson; Glyn Alan Hughes; Werngard Czechtizky; Hongtao Zhao; Emelyne DIERS; Tristan REUILLON; Stefan Von Berg; Christian Tyrchan; Samy CHAMMAA TÓRTOLA
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2024-01-09
Filing date: 2025-01-08
Publication date: 2025-07-17
Anticipated expiration: 2026-07-09

Abstract

The present invention relates to substituted benzyl piperidines of Formula (I) as well as to their use as TRPV4 antagonists for use in treating e.g. inflammatory, respiratory, metabolic, dermatological, skeletal, neuromuscular or genetic diseases or disorders, cancer, or pain.

Description

BENZYLPIPERIDINE DERIVATIVES AS TRP4 ANTAGONISTS FOR THE TREATMENT OF INFLAMMATORY DISEASES

CROSS-REFERENCE TO RELATED PATENT APPLICATION

This specification claims the benefit of priority to European Patent Application No. 24150832.4 (filed 9 January 2024). The entire contents of the above-referenced patent application is incorporated by reference into this specification for all purposes.

FIELD

The present disclosure relates to substituted benzyl piperidines and their use as TRPV4 antagonists. The present disclosure further relates to pharmaceutical compositions comprising such compounds, and use of such compounds to treat a TRPV4-associated disease or disorder.

BACKGROUND

Transient Receptor Potential Vanilloid 4 (TRPV4) belongs to the Transient Receptor Potential (TRP) family that includes 28 transmembrane cation-permeable channels. TRPV4 consists of 871 amino acid residues in a tetrameric structure with 6 transmembrane a-helices (S1-S6) and a pore loop found between S5 and S6. The species differences are limited with approximately 95% identity human versus rat and mouse. TRPV4 has been shown to be activated by warm temperature (>27°C), lipid arachidonic acids and its epoxy eicosatrienoic acid metabolites, changes in extracellular osmolarity, low pH, inflammation, and natural and synthetic agonists (e.g., GSK1016790A). See, e.g., White et al., Physiol Rev 96:911-973 (2016). The apo cryo- EM structure of Xenopus tropicalis TRPV4 at 3.8- A resolution has been published in Deng et al., Nat Struct Mol Biol 25:252-260 (2018).

TRPV4 overactivation is associated with numerous pathologies, including inflammation, respiratory diseases, metabolic diseases and disorders, dermatological diseases and disorders, skeletal diseases and disorders, neuromuscular diseases and disorders, cancers, and genetic diseases and disorders. See, e.g., WO 2013/152109, WO 2014/209947, WO 2017/177200, and WO 2024/011214; Rosenbaum et al., Int J Mol Sci 21(11):3837 (2020); Lawhorn et al., Bioorganic Med Chem Lett 30(8): 127022 (2020), Pu et al., Acta Biochem. Pol 69( 1 ) : 51 (2022), Orfali et al, Int. J. Mol. Sci. 25(19): 10551 (2024). For example, activation of TRPV4 in the lung has been shown to cause pulmonary edema (endothelial permeability), cough, contraction of smooth muscle cells, and release of adenosine triphosphate (ATP). Blocking of TRPV4 by small molecule antagonists has been shown to reduce eosinophilia in ovalbumin challenged rat and in addition reduce cough in TRPV4 agonist challenged Guinea pig (Wortley et al., Handb Exp Pharmacol 237:213-241 (2017)). In addition, TRPV4 antagonism has been suggested to suppress the metastasis of hepatocellular carcinoma (Cell Death and Disease (2023) 14:379), reduce invasiveness of colorectal cancer (BMC Cancer (2021) 21 : 1264) and attenuate pathological cardiac hypertrophy by enhancing coronary angiogenesis (Hypertension. (2023) 80: 2345). Thus, compounds having TRPV4 antagonist activity may be beneficial for individuals with TRPV4-associated diseases or disorders.

To date, only one TRPV4 antagonist, GSK2798745, has advanced into clinical trials (see, e.g., NCT02497937). GSK2798745 was safe and well-tolerated in heart failure patients, but did not result in a significant effect on pulmonary gas diffusion (Stewart et al., Eur J Heart Fail 22:1641-1645 (2020)). Subsequent studies indicate this may be due to a major circulating human metabolite of GSK2798745 being significantly less potent and limiting target engagement (Pero et al., ACS Med Chem Lett 12:1498-1502 (2021)).

There remains a need for TRPV4 antagonists, in particular TRPV4 antagonists having appropriate properties, such as potency, for treating TRPV4-associated diseases or disorders.

SUMMARY

The present disclosure provides substituted benzyl piperidine compounds and their use as TRPV4 antagonists. In some embodiments, the disclosure provides a compound which is a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is: a) a 5-membered heteroaryl selected from pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole and tetrazole, wherein ring A is optionally substituted with Ci-3alkyl or C2-4alkoxy alkyl; or

(ring A¹) wherein ring A¹ is a 5-6 membered saturated heterocycle containing the nitrogen atom and oxo substituent depicted, and optionally containing 1 additional heteroatom selected from nitrogen and oxygen, wherein ring A¹ is optionally substituted with C1-3 alkyl; wherein (R¹) indicates the point of attachment to R¹;

R¹ is selected from R^lx, -Ci-3alkylene-R^lx, Ci-3alkyl and Ci-shaloalkyl;

R^lx is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered saturated heterocycle, and C3-4cycloalkyl, wherein each R^lx is optionally substituted with 1, 2 or 3 occurrences of R^ly; each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-salkyl, nitrile, Ci-3alkoxy, Ci-shaloalkoxy, C3-4cycloalkoxy, and -O-Het¹, wherein Het¹ is a 3-4 membered saturated heterocycle optionally substituted with C1-3 alkyl;

R² is selected from Ci-shaloalkoxy, Ci-3alkoxy, C3-4cycloalkyl, C3-4cycloalkoxy, and halo;

R³ is C1-4 alkyl substituted with one or two occurrences of hydroxyl.

In some embodiments, the disclosure provides a compound which is a compound of Formula (II):

Formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring A is: a) a 5-membered heteroaryl selected from pyrazole, imidazole and triazole, wherein ring

A is optionally substituted with one occurrence of Ci-3alkyl or C2-4alkoxyalkyl, or

R¹ is selected from phenyl and pyridine, wherein R¹ is optionally substituted with 1 or 2 occurrences of R^ly; each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-salkyl, nitrile, Ci- shaloalkoxy and C3-4cycloalkoxy; and

R² is selected from Ci-shaloalkoxy, C3-4cycloalkyl and halo.

In some embodiments, the disclosure provides a compound which is a compound as found in Table 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a composition comprising a compound described herein. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

In some embodiments, the disclosure provides a method of inhibiting activity of TRPV4, comprising contacting TRPV4 with a compound or a composition described herein.

In some embodiments, the disclosure provides a method of inhibiting activity of TRPV4 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or a composition described herein to the subject.

In some embodiments, the disclosure provides a compound or a composition described herein for use in therapy.

In some embodiments, the disclosure provides a compound or a composition described herein for use in a method of treating or preventing a TRPV4-associated disease or disorder.

In some embodiments, the disclosure provides the use of a compound or a composition described herein in the manufacture of a medicament for treating or preventing a TRPV4- associated disease or disorder.

In some embodiments, the disclosure provides a method of treating or preventing a TRPV4- associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or a composition described herein to the subject. In some embodiments, the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, cancer, a genetic disease or disorder, or combination thereof. In some embodiments, the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, neuropathic pain, chronic vulvar pain, colitis, sclerosis, obesity, diabetes, lung ischemia reperfusion injury, cystic fibrosis, or combination thereof.

In some embodiments, the TRPV4-associated disease or disorder is cancer. In some embodiments, the cancer is hepatocellular carcinoma, colon cancer, colorectal cancer or nonsmall cell lung cancer.

In some embodiments, the TRPV4-associated disease or disorder is a cardiovascular disease or disorder. In some embodiments, the cardiovascular disease or disorder is hypertrophic cardiomyopathy.

DETAILED DESCRIPTION

Definitions

Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

As used herein, the terms "comprising" (and any variant or form of comprising, such as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and "has"), "including" (and any variant or form of including, such as "includes" and "include") or "containing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps.

The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise.

Numeric ranges are inclusive of the numbers defining the range. For example, as used herein, "between" is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y.

The prefix C_{x y}, where x and y are integers, indicates the numerical range of carbon atoms that are present in a moiety.

As used herein the term “alkyl” refers to a saturated, linear or branched hydrocarbon radical having the specified number of carbon atoms. Examples of C1-3 alkyl groups include methyl (Me), ethyl (Et), n-propyl (nPr), and i-propyl (iPr). Examples of C1-4 alkyl groups include methyl (Me), ethyl (Et), n-propyl (nPr), i-propyl (iPr), n-butyl (nBu), i-butyl (iBu), s-butyl (sBu), and t-butyl (tBu).

As used herein the term “alkylene” refers to a saturated, linear or branched bivalent hydrocarbon radical having the specified number of carbon atoms. In some embodiments, an alkylene group may be linear. Examples of C1-3 alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-) and n-propylene (-CH2CH2CH2-).

The term "alkoxy" refers to linear or branched oxy-containing moieties, each having an alkyl portion as described above, having the specified number of carbon atoms.

The term "alkoxyalkyl" refers to alkyl moieties having one or more alkoxy moieties attached to the alkyl moiety, wherein the alkoxyalkyl moiety has the specified number of carbon atoms. For example, C2-4alkoxyalkyl refers to an alkoxyalkyl moiety having between 2 and 4 carbon atoms in total. Examples of C2-4alkoxyalkyl include -CH2OCH3, -(CEh^OCEE, - (CH2)₃OCH₃ and -(CH₂)2OCH₂CH3. The term "cycloalkyl" refers to a saturated, cyclic hydrocarbon radical having the specified number of carbon atoms. In some embodiments, a cycloalkyl may be monocyclic. Examples of C3-4 cycloalkyl groups include cyclopropyl and cyclobutyl.

The term “cycloalkoxy” refers to a cycloalkyl having the specified number of carbon atoms, connected to an oxy moiety. Examples of C3-4 cycloalkoxy groups include cyclopropoxy and cyclobutoxy, which may be depicted as:

The term "halo" refers to a moiety containing a halogen, i.e., fluorine, chlorine, bromine, or iodine. In some embodiments, halo refers to fluoro or chloro. The term "haloalkyl" refers to an alkyl moiety having the specified number of carbon atoms, in which one or more of the alkyl carbon atoms is substituted with one or more halo groups. In some embodiments, the haloalkyl is a monohaloalkyl, dihaloalkyl, or polyhaloalkyl. Examples of Ci-3haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl (e.g. - CH2CHF2), trifluoroethyl (e.g. -CH2CF3), difluor opropyl, di chloroethyl and di chloropropyl.

The term “haloalkoxy” refers to an alkoxy moiety having the specified number of carbon atoms, in which one or more of the alkyl carbon atoms is substituted with one or more halo groups. Examples of Ci-3haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy (e.g. - OCH2CHF2), trifluoroethoxy (e.g. -OCH2CF3), difluoropropoxy, di chloroethoxy and dichloropropoxy.

As used herein the term “heterocycle” refers to a ring structure containing the specified numbered of ring atoms (referred to as “members”), wherein one or more of the ring atoms is a heteroatom (e.g., oxygen, nitrogen, and/or sulfur, unless otherwise defined), with the remaining ring atoms being carbon. A heterocycle may be saturated or unsaturated, unless otherwise specified. A heterocycle may be monocyclic or multicyclic (e.g. bicyclic), unless otherwise specified. In some embodiments, a heterocycle described herein is monocyclic. In some embodiments, a heterocycle described herein is a saturated heterocycle. The term "heterocycle" includes all possible isomeric forms of the heterocycles. In some embodiments, a heterocycle described herein comprises at least one N, S, or O. Examples of heterocycles are described herein. Unless otherwise specified, a heterocycle may be substituted on a carbon atom or a nitrogen atom.

The term "heteroaryl" refers to a fully unsaturated (“aromatic”) ring structure containing the specified numbered of ring atoms (referred to as “members”), wherein one or more of the ring atoms is a heteroatom (e.g., nitrogen, sulfur, and/or oxygen, unless defined otherwise) with the remaining ring atoms being carbon. In some embodiments, a heteroaryl may be monocyclic. Exemplary 5-membered heteroaryls include pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole and tetrazole. Exemplary 6-membered heteroaryls include pyridine, pyrimidine and pyrazine. Unless otherwise specified, a heteroaryl may be substituted on a carbon or nitrogen atom.

The term "nitrile" refers to a moiety in which a carbon atom is triple-bonded to a nitrogen atom (-ON), also known as a "cyano" group.

The term “oxo” refers to a double bonded oxygen atom (i.e. “=O”).

The term "substituted" means that any one or more hydrogen atoms on a carbon on nitrogen atom is replaced with any suitable substituent, provided that the normal valency is not exceeded and the replacement results in a stable compound. Suitable substituents are described herein.

Certain embodiments of this disclosure include a moiety which is said to be “optionally substituted”. In such embodiments, the moiety may be either (1) not substituted, or (2) substituted. In further embodiments, said moiety is substituted with the listed substituents. In other further embodiments, said moiety is unsubstituted.

The use of “ (a “wavy line”) in formulae of this specification denotes the point of covalent attachment to a chemical moiety. Unless otherwise specified, a moiety with two points of covalent attachment within a formula, may be in either orientation with respect to the formula. For example, the following option for ring A in a compound of Formula (I): could be in the following two orientations within the compound:

In some instances, a moiety with two points of covalent attachment within a formula may contain a wavy line annotated with a variable in brackets (e.g. in which case the point of attachment at that position of the moiety is to the annotated variable, such that the orientation of the moiety is fixed. For example, the following option for ring A in a compound of Formula (I): refers to the following structure:

Compounds

In some embodiments, a compound described herein is a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is: a) a 5-membered heteroaryl selected from pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole and tetrazole, wherein ring A is optionally substituted (on a carbon atom or, if available, a nitrogen atom) with Ci-salkyl or C2-4alkoxyalkyl; or b)

(ring A¹) wherein ring A¹ is a 5-6 membered saturated heterocycle containing the nitrogen atom and oxo substituent depicted, and optionally containing 1 additional heteroatom selected from nitrogen and oxygen, wherein ring A¹ is optionally substituted (on a carbon atom or, if available, a nitrogen atom) with C1-3 alkyl; wherein (R¹) indicates the point of attachment to R¹;

R¹ is selected from R^lx, -Ci-3alkylene-R^lx, Ci-3alkyl and Ci-shaloalkyl;

R^lx is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered saturated heterocycle, and C3-4cycloalkyl, wherein each R^lx is optionally substituted with 1, 2 or 3 occurrences of R^ly; each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-salkyl, nitrile, Ci-3alkoxy, Ci- shaloalkoxy, C3-4cycloalkoxy, and -O-Het¹, wherein Het¹ is a 3-4 membered saturated heterocycle optionally substituted with C1-3 alkyl;

R³ is C1-4 alkyl substituted with one or two occurrences of hydroxyl.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A):

Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹, R² and R³ are as defined for Formula (I).

In some embodiments, a compound described herein is a compound of Formula (I) or (I-A). In some embodiments, a compound described herein is a pharmaceutically acceptable salt of compound of Formula (I) or (I-A).

In some embodiments, ring A is a 5-membered heteroaryl selected from pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole and tetrazole, wherein ring A is optionally substituted with Ci-salkyl or C2-4alkoxy alkyl. The points of attachment of the 5-membered heteroaryl to the adjacent moieties present in Formula (I) or (I-A) (i.e. the R¹ moiety and the phenyl moiety) may be via a carbon atom or a nitrogen atom of the heteroaryl. In some embodiments, ring A is selected from pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole and thiadiazole, optionally substituted as described herein. In further embodiments, ring A is selected from pyrazole, imidazole, triazole, oxazole and oxadiazole, optionally substituted as described herein. In further embodiments, ring A is selected from pyrazole, imidazole, triazole, oxazole and oxadiazole, optionally substituted as described herein. In further embodiments, ring A is selected from pyrazole, imidazole and triazole, optionally substituted as described herein.

In some embodiments, ring A is selected from: wherein the ring is optionally substituted (on a carbon atom or, where available, a nitrogen atom) with Ci-3alkyl or C2-4alkoxy alkyl. In such embodiments, ring A can be in either orientation with respect to Formula (I) or (I-A). In further embodiments, ring A is selected from:

wherein R^Ax is H, Ci-3alkyl or C2-4alkoxyalkyl and R^A is H or Ci-3alkyl, and (R¹) indicates the point of attachment to R¹. In some embodiments, R^A is H. In some embodiments, R^A is Ci- 3alkyl, optionally methyl. In some embodiments, R^Ax is Ci-3alkyl, optionally methyl or ethyl. In some embodiments, R^Ax is C2-4alkoxyalkyl, optionally -(CH2)2OCH3.

In some embodiments, ring A is selected from the following moieties: wherein (R¹) indicates the point of attachment to R¹, and wherein R^A and R^Ax are each independently Ci-3alkyl or C2-4alkoxy alkyl. In some embodiments, R^A is Ci-3alkyl, optionally methyl. In some embodiments, R^Ax is Ci-3alkyl, optionally methyl or ethyl. In some embodiments, R^Ax is C2-4alkoxyalkyl, optionally -(CH2)2OCH3.

In some embodiments, ring A is ring A¹: wherein ring A¹ is a 5-6 membered saturated heterocycle containing the nitrogen atom and oxo substituent depicted, and optionally containing 1 additional heteroatom selected from nitrogen and oxygen, wherein ring A¹ is optionally substituted with C1-3 alkyl; wherein (R¹) indicates the point of attachment to R¹. In some embodiments, ring A¹ is a 5-6 membered saturated heterocycle containing the nitrogen atom and oxo substituent depicted, and further containing 1 additional heteroatom selected from nitrogen and oxygen. In some embodiments, the additional heteroatom is nitrogen. The point of attachment of ring A¹ to R¹ may be via a carbon atom or a nitrogen atom of ring A¹. In some embodiments, the point of attachment of ring A¹ to R¹ is via a nitrogen.

In some embodiments, ring A is selected from: wherein R^A1 is H or C1-3 alkyl, R^A2 is C1-3 alkyl. In such embodiments, ring A can be in either orientation with respect to Formula (I) or (I-A). In some embodiments, R^A1 is H. In some embodiments, R^A1 is C1-3 alkyl, optionally methyl. In some embodiments, R^A2 is methyl.

In some embodiments, ring A is selected from: wherein R^A1 is H or C1-3 alkyl, R^A2 is C1-3 alkyl, and (R¹) indicates the point of attachment to R¹. In some embodiments, R^A1 is H. In some embodiments, R^A1 is C1-3 alkyl, optionally methyl. In some embodiments, R^A2 is methyl. In further embodiments, ring A is In some embodiments, R¹ is R^lx. In some embodiments, R¹ is -Ci-3alkylene-R^lx; optionally wherein the Ci-3alkylene is linear. In some embodiments, R^lx is phenyl. In some embodiments, R^lx is a 5-6 membered heteroaryl. In some embodiments, R^lx is a 5-6 membered heteroaryl containing 1 or 2 nitrogen atoms. In some embodiments, R^lx is pyridine or pyrazole. In some embodiments, R^lx is pyridine. In some embodiments, R^lx is a 5-6 membered saturated heterocycle. In some instances, the 5-6 membered saturated heterocycle may contain 1-2 nitrogen atoms and/or an oxygen atom (e.g. tetrahydropyran, tetrahydrofuran, morpholine, piperidine, piperazine). In some embodiments, R^lx is tetrahydropyran. In some embodiments, R^lx is a C3-4cycloalkyl, such as cyclobutyl.

In some embodiments, R^lx is substituted with 1 occurrence of R^ly, wherein R^ly is as defined herein. For example, the 1 occurrence of R^ly may be independently selected from halo, Ci- shaloalkyl, Ci-3alkyl, nitrile, Ci-3haloalkoxy and C3-4cycloalkoxy. The 1 occurrence of R^ly may be selected from halo, Ci-shaloalkyl and Ci-3alkyl. In some embodiments, the 1 occurrence of R^ly is selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy. In some embodiments, the 1 occurrence of R^ly is selected from fluoro, chloro, -CF3 and methyl.

In some embodiments, R^lx is substituted with 2 occurrences of R^ly, wherein R^ly is as defined herein. For example, the 2 occurrences of R^ly may each be independently selected from halo, Ci-3haloalkyl, Ci-3alkyl, nitrile, C 1-3 haloalkoxy and C3-4cycloalkoxy. The 2 occurrences of R^ly may each be independently selected from halo, Ci-shaloalkyl and Ci-3alkyl. One occurrence of R^ly may be selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, Ci-3haloalkoxy and C3-4cycloalkoxy, and the other occurrence of R^ly may be selected from halo, Ci-shaloalkyl and Ci-3alkyl. In some embodiments, the 2 occurrences of R^ly may each be independently selected from fluoro, chloro, -CF3 and methyl. In some embodiments, one occurrence of R^ly is selected from fluoro, chloro, -CF3 and methyl, and the second occurrence of R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy.

In some embodiments, each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, Ci-3alkoxy, Ci-3haloalkoxy and C3-4cycloalkoxy. In some embodiments, each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, C 1-3 haloalkoxy and C3- 4cycloalkoxy. In some embodiments, each R^ly is independently selected from halo, Ci- shaloalkyl and Ci-3alkyl. In some embodiments, each R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy. In some embodiments, each R^ly is independently selected from fluoro, chloro, -CF3, methyl.

In some embodiments, R^lx is substituted with 0 occurrences of R^ly.

In some embodiments, R¹ is Ci-3alkyl. In some embodiments, R¹ is Ci-shaloalkyl.

In some embodiments, R¹ is phenyl optionally substituted with 1, 2 or 3 occurrences of R^ly, wherein R^ly is as defined herein. In some embodiments, R¹ is unsubstituted phenyl. In some embodiments, R¹ is phenyl substituted with 1 occurrence ofR^ly (e.g. wherein R^ly is as defined herein. In some embodiments, R¹ is phenyl substituted with 2 occurrences of R^ly (e.g. wherein

R^ly is as defined herein. For example, the 2 occurrences of R^ly may be: (i) halo and halo (e.g.

F and F, or F and Cl), (ii) halo (e.g. F or Cl) and nitrile, or (iii) methyl and nitrile. In some embodiments, the 2 occurrences of R^ly may be halo and halo (e.g. F and F, or F and Cl).

In some embodiments, R¹ is pyridine optionally substituted with 1, 2 or 3 occurrences of R^ly, wherein R^ly is as defined herein. In some embodiments, R¹ is unsubstituted pyridine. In some embodiments, R¹ is . In some embodiments, R¹ is

In some embodiments, R¹ is pyridine substituted with 1 occurrence of R^ly, wherein R^ly is as defined herein. In some embodiments, R¹ is wherein R^ly is as defined herein. In some embodiments, wherein R^ly is as defined herein. In such embodiments, R^ly may be halo (e.g. fluoro) or Ci-shaloalkyl (e.g. -CF3). In some embodiments, R¹ is pyridine substituted with 2 occurrences of R^ly, wherein R^ly is as defined herein. In some embodiments, R¹ is wherein R^ly is as defined herein. In such embodiments, each R^ly may be halo (e.g. fluoro).

In some embodiments, R² is selected from Ci-shaloalkoxy, C3-4cycloalkyl and halo. In some embodiments, R² is selected from C3-4cycloalkyl and halo. In some embodiments, R² is selected from -OCHF2, cyclopropyl and chloro. In some embodiments, R² is selected from cyclopropyl and chloro.

In some embodiments, R³ is C3-4 alkyl substituted with one or two occurrences of hydroxyl, wherein one occurrence of the hydroxyl is at a tertiary carbon. In other words, the C3-4 alkyl contains a tertiary carbon, and the hydrogen atom on this tertiary carbon is replaced with a hydroxyl moiety. In further embodiments, R³ is C3-4 alkyl substituted with two occurrences of hydroxyl, wherein one occurrence of the hydroxyl is at a tertiary carbon. In further embodiments, R³ is In further embodiments, R³ is

In some embodiments, one or more hydrogens present in the compound are deuterated. For example, the compound of Formula (I) or Formula (I-A), or a pharmaceutically acceptable salt thereof, may be as depicted below:

Formula (I-J) Formula (I-A-r/) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹, R² and R³ are as defined for Formula (I) or (I-A).

In some embodiments, a compound described herein is a compound of Formula (II):

Formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring A is: a) a 5-membered heteroaryl selected from pyrazole, imidazole and triazole, wherein ring A is optionally substituted (at a carbon atom or, if available, a nitrogen atom) with one occurrence of Ci-3alkyl or C2-4alkoxyalkyl, or

R¹ is selected from phenyl and pyridine, wherein R¹ is optionally substituted with 1 or 2 occurrences of R^ly; each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-salkyl, nitrile, Ci-shaloalkoxy and C3-4cycloalkoxy; and

R² is selected from Ci-shaloalkoxy, C3-4cycloalkyl and halo.

In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II- A):

Formula (II-A) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R² are as defined for Formula (II). In some embodiments, a compound described herein is a compound of Formula (II) or (II-A). In some embodiments, a compound described herein is a pharmaceutically acceptable salt of compound of Formula (II) or (II-A).

In some embodiments, ring A is a 5-membered heteroaryl selected from pyrazole, imidazole and triazole, wherein ring A is optionally substituted with Ci-3alkyl or C2-4alkoxy alkyl. The points of attachment of the 5-membered heteroaryl to the adjacent moi eties present in Formula (II) or (II-A) (i.e. the R¹ moiety and the phenyl moiety) may be via a carbon atom or a nitrogen atom in the heteroaryl.

In some embodiments, ring A is selected from the following moieties: wherein (R¹) indicates the point of attachment to R¹, and wherein R^A and R^Ax are each independently Ci-3alkyl or C2-4alkoxy alkyl. In some embodiments, R^A is Ci-3alkyl, optionally methyl. In some embodiments, R^Ax is Ci-3alkyl, optionally methyl or ethyl. In some embodiments, R^Ax is C2-4alkoxyalkyl, optionally -(CFh^OCF .

In some embodiments, ring

In some embodiments, R¹ is substituted with 1 occurrence of R^ly, wherein R^ly is as defined herein. For example, the 1 occurrence of R^ly may be independently selected from halo, Ci- shaloalkyl, Ci-3alkyl, nitrile, Ci-3haloalkoxy and C3-4cycloalkoxy. The 1 occurrence of R^ly may be selected from halo, Ci-shaloalkyl and Ci-3alkyl. In some embodiments, R^ly is selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy. In some embodiments, R^ly is selected from fluoro, chloro, -CF3 and methyl.

In some embodiments, R¹ is substituted with 2 occurrences of R^ly, wherein R^ly is as defined herein. For example, the 2 occurrences of R^ly may be independently selected from halo, Ci- shaloalkyl, Ci-3alkyl, nitrile, Ci-shaloalkoxy and C3-4cycloalkoxy. The 2 occurrences of R^ly may be independently selected from halo, Ci-shaloalkyl and Ci-3alkyl. One occurrence of R^ly may be selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, Ci-3haloalkoxy and C3- 4cycloalkoxy, and the other occurrence of R^ly may be selected from halo, Ci-shaloalkyl and Ci-3alkyl. In some embodiments, the 2 occurrences of R^ly may each be independently selected from fluoro, chloro, -CF3 and methyl. In some embodiments, one occurrence of R^ly is selected from fluoro, chloro, -CF3 and methyl, and the second occurrence of R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy.

In some embodiments, each R^ly is independently selected from halo, Ci-shaloalkyl and Ci- 3alkyl. In some embodiments, each R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy. In some embodiments, each R^ly is independently selected from fluoro, chloro, -CF3 and methyl.

In some embodiments, R¹ is substituted with 0 occurrences of R^ly.

In some embodiments, R¹ is phenyl. In some embodiments, R¹ is unsubstituted phenyl.

In some embodiments, R¹ is phenyl substituted with 1 occurrence of R^ly (e.g. wherein R^ly is as defined herein.

In some embodiments, R¹ is phenyl substituted with 2 occurrences of R^ly (e.g. wherein R^ly is as defined herein. For example, the 2 occurrences of R^ly may be: i) halo and halo (e.g. F and F, or F and Cl), (ii) halo (e.g. F or Cl) and nitrile, or (iii) methyl and nitrile. In some embodiments, the 2 occurrences of R^ly may be halo and halo (e.g. F and F, or F and Cl).

In some embodiments, R¹ is pyridine. In some embodiments, R¹ is unsubstituted pyridine. In some embodiments, R¹ is . In some embodiments, R¹ is . In some embodiments, R¹ is pyridine substituted with 1 occurrence of R^ly, wherein R^ly is as defined herein. In some embodiments, R¹ is wherein R^ly is as defined herein. In some embodiments, wherein R^ly is as defined herein. In such embodiments, R^ly is halo (e.g. fluoro) or Ci-shaloalkyl (e.g. -CF3). In some embodiments, R¹ is pyridine substituted with 2 occurrences of R^ly, wherein R^ly is as defined herein. In some embodiments,

R¹ is wherein R^ly is as defined herein; for example, each R^ly may be halo (e.g. fluoro).

In some embodiments, R² is selected from C3-4cycloalkyl and halo. In some embodiments, R² is selected from -OCHF2, cyclopropyl and chloro. In some embodiments, R² is selected from cyclopropyl and chloro.

In some embodiments, one or more hydrogens present in the compound are deuterated. For example, the compound of Formula (II) or Formula (II-A), or a pharmaceutically acceptable salt thereof, may be as depicted below:

Formula (II-J) Formula (II-A-t/) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R² are as defined for Formula (II) or (II-A).

In some embodiments, a compound described herein is a compound as shown in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound described herein is a compound of Table 1. In some embodiments, a compound described herein is a pharmaceutically acceptable salt of a compound of Table 1.

Table 1. Compounds.

The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopes of nitrogen include ¹⁵N. Optionally, isotopes may be present in positions as specified in formulae described herein. The compounds disclosed herein may contain one or more chiral centres. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers and diastereoisomers of the compound depicted. For example, a compound containing a chiral carbon atom (a stereocentre) is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R). In compounds depicted herein, graphical representation of stereocentres such as and 'or' may be used to describe the configuration of the stereochemical centres present in the structure. In general, the label '&' at a stereocentre means the configuration at that stereocentre is a mixture of both (R) and (S); and a label 'or' means the configuration at that stereocentre is either (S) or (R). In general, for structures where all of the stereocentres are designated as '&', the structure is named with a “rac-” prefix. For structures where all of the stereocentres are designated as 'or', the structure is named with a “rel-” prefix. In general, compounds are named using the descriptors (RS) and (SR) to denote general '&' centres for chemical structures with multiple chiral centres where only some are designated as '&', and the descriptors (R*) and (S*) are used to denote the general 'or' centres for chemical structures with multiple chiral centres where only some are designated as 'or'. In general, the descriptors (r) and (s) are used to describe the absolute configuration of any pseudoasymmetric centres in the structures depicted herein.

The compound described herein may exist in various forms, for example as conformers, rotamers and tautomers. In cases where compounds may exist in tautomeric forms (e.g. keto/enol, amide/iminol), whether existing in equilibrium or predominantly in one form, depiction of one tautomer is intended to encompass the other tautomer.

The compounds of the present disclosure may exist in salt form or in non-salt form (i.e., as a free base), and the present disclosure covers both salt forms and non-salt forms. For example, in some embodiments, a compound described herein is a pharmaceutically acceptable salt. In other embodiments, a compound described herein is in a non-salt form.

The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. A suitable pharmaceutically acceptable salt of a compound described herein is, for example, an acid-addition salt or a base-addition salt. An acid addition salt of a compound described herein may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. A base-addition salt of a compound described herein may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person. A further suitable pharmaceutically acceptable salt is, for example, a salt formed within a patient’s body after administration of a compound described herein to the patient.

Compositions

In some embodiments, a compound described herein is included in a composition. In some embodiments, the disclosure provides a composition configured to be administered to a subject in need thereof.

In some embodiments, the composition provided herein is capable of being adapted for administration via any suitable route by selection of appropriate excipients and dosage of the compound effective for the treatment intended, e.g., a Transient Receptor Potential Vanilloid 4 (TRPV4)-associated disease or disorder. For example, compositions described herein can be prepared in a form suitable for administration orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, or rectally. In some embodiments, the composition is a solid or a liquid, or both, and is further formulated with the compound as a unit-dose composition.

In some embodiments, the composition comprises a compound of the present disclosure, and further comprises one or more pharmaceutically acceptable excipients. Exemplary pharmaceutically acceptable excipients are known to one of ordinary skill in the art and include but are not limited to diluents, disintegrants, binding agents and adhesives, wetting agents, lubricants, anti-adherents, surfactants, humectants, plasticizers, crystallization inhibitors, bulk filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, colorants, and flavorants. Methods and uses

Compounds described herein have appropriate properties for use as TRPV4 antagonists and for treating TRPV4-associated diseases or disorders. For example, compounds described herein inhibit TRPV4 (see e.g. IC50 values presented in Table 3 herein). Furthermore, compounds described herein may have selectivity for TRPV4 and/or may have good bioavailability.

In some embodiments, the disclosure provides a method of inhibiting activity of TRPV4, comprising contacting TRPV4 with a compound of the present disclosure, or with a composition comprising the compound as described herein. In some embodiments, the method is performed in vivo. In some embodiments, the method is performed in vitro.

The term "inhibiting activity" refers to a reduction or blockade of activity of a target, e.g. TRPV4, relative to the activity in an untreated or control sample, and does not require total elimination of an activity.

In some embodiments, the disclosure provides a method of treating or preventing a TRPV4- associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of the present disclosure, or with a composition comprising the compound, as described herein. In some embodiments, the subject is a mammalian subject. In some embodiments, the subject is a human subject. In some embodiments, the subject is an animal subject, e.g., mouse, rat, rabbit, pig, or nonhuman primate (NHP) such as monkey. In some embodiments, the method is a method of treating a TRPV4-associated disease or disorder.

The term "therapeutically effective amount" means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The therapeutically effective amount of an active ingredient will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

In some embodiments, the disclosure provides a compound or a composition described herein for use in therapy. The term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve or ameliorate one, some, or all of its symptoms, or to correct or compensate for the underlying pathology. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner. The term “treatment” may be used synonymously with “therapy”. Similarly, the terms “treat” and “treating” can be regarded as “applying therapy” where “therapy” is as defined herein.

The term “prevention” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

In some embodiments, the disclosure provides a compound or a composition described herein for use in a method of treating or preventing a TRPV4-associated disease or disorder. In some embodiments, a compound or a composition described herein is for use in a method of treating a TRPV4-associated disease or disorder.

In some embodiments, the disclosure provides the use of a compound or a composition described herein in the manufacture of a medicament for treating or preventing a TRPV4- associated disease or disorder. In some embodiments, the use of a compound or a composition described herein is in the manufacture of a medicament for treating a TRPV4-associated disease or disorder.

In some embodiments, the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, cancer, a genetic disease or disorder, pain, or a combination thereof.

In some embodiments, the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, or combination thereof.

In some embodiments, the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, neuropathic pain, chronic vulvar pain, colitis, sclerosis, obesity, diabetes, lung ischemia reperfusion injury, cystic fibrosis, or combination thereof.

In some embodiments, the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, colitis, sclerosis, obesity, diabetes, or combination thereof. TRPV4-associated diseases and disorders are further discussed in, e.g., WO 2013/152109, WO 2014/209947, and WO 2017/177200.

In some embodiments, the TRPV4-associated disease or disorder is cancer. In some embodiments, the cancer is hepatocellular carcinoma, colon cancer, colorectal cancer, nonsmall cell lung cancer. In some embodiments, the cancer is hepatocellular carcinoma or colorectal cancer.

In some embodiments, the TRPV4-associated disease or disorder is a cardiovascular disease or disorder. In some embodiments, the cardiovascular disease or disorder is hypertrophic cardiomyopathy. This may also be referred to as pathological cardiac hypertrophy.

Synthetic methods

The compounds described herein may be prepared according to procedures exemplified by the specific examples provided herein. Moreover, by utilising the procedures described herein and variants thereof, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present claims. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

The compounds exemplified herein may also be isolated in the form of their pharmaceutically acceptable salts, such as those described herein. It may be necessary to protect reactive functional groups in intermediates used in the preparation of compounds described herein to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by P. G. M. Wuts in “Greene’s Protective Groups in Organic Synthesis”, Fifth Edition., John Wiley & Sons Inc., 2014, may be used.

The present disclosure is not intended to be limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the disclosure that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the disclosure that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

The entire contents of all publications, patents, and patent applications referenced herein are hereby incorporated herein by reference.

Numbered Embodiments

1. A compound which is a compound of Formula (I):

R¹ is selected from R^lx, -Ci-3alkylene-R^lx, Ci-3alkyl and Ci-shaloalkyl;

R³ is C1-4 alkyl substituted with one or two occurrences of hydroxyl.

2. The compound of embodiment 1, wherein the compound is a compound of Formula

(I-A):

Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹, R² and R³ are as defined in embodiment 1.

3. The compound of embodiment 1 or 2, wherein ring A is selected from pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole and tetrazole, optionally substituted with Ci-salkyl or C2-4alkoxy alkyl. 4. The compound of any preceding embodiment, wherein ring A is selected from pyrazole, imidazole, triazole, oxazole and oxadiazole, optionally substituted with Ci-3alkyl or C2-4alkoxy alkyl. 5. The compound of any preceding embodiment, wherein ring A is selected from pyrazole, imidazole and triazole, optionally substituted with Ci-3alkyl or C2-4alkoxy alkyl.

6. The compound of any of embodiments 1-4, wherein ring A is selected from: wherein the ring is optionally substituted with Ci-3alkyl or C2-4alkoxy alkyl.

7. The compound of any of embodiments 1-4, wherein ring A is selected from: wherein R^Ax is H, Ci-3alkyl or C2-4alkoxyalkyl and R^A is H or Ci-3alkyl, and (R¹) indicates the point of attachment to R¹.

8. The compound of embodiment 7, wherein R^A is H. 9. The compound of any of embodiments 1-5, wherein ring A is selected from the following moieties: wherein (R¹) indicates the point of attachment to R¹, and wherein R^A and R^Ax are each independently Ci-3alkyl or C₂-4alkoxy alkyl.

10. The compound of embodiment 7 or 9, wherein R^A is Ci-3alkyl, optionally methyl.

11. The compound of embodiment 7 or 9, wherein R^Ax is Ci-3alkyl, optionally methyl or ethyl.

12. The compound of embodiment 7 or 9, wherein R^Ax is C2-4alkoxyalkyl, optionally - (CH₂)₂OCH₃.

13. The compound of embodiment 1 or 2, wherein ring A is:

(ring A¹) wherein ring A¹ is a 5-6 membered saturated heterocycle containing the nitrogen atom and oxo substituent depicted, and optionally containing 1 additional heteroatom selected from nitrogen and oxygen, wherein ring A¹ is optionally substituted with C1-3 alkyl; wherein (R¹) indicates the point of attachment to R¹; and

R¹ is selected from R^lx, -Ci-3alkylene-R^lx, Ci-3alkyl and Ci-3haloalkyl. 14. The compound of embodiment 13, wherein the 1 additional heteroatom is nitrogen, optionally wherein the point of attachment of ring A¹ to R¹ is via said nitrogen.

15. The compound of embodiment 1, 2 or 13, wherein ring A is selected from: wherein R^A1 is H or C1-3 alkyl and R^A2 is C1-3 alkyl.

16. The compound of embodiment 1, 2 or 13, wherein ring A is selected from: wherein R^A1 is H or C1-3 alkyl, R^A2 is C1-3 alkyl, and (R¹) indicates the point of attachment to R¹.

17. The compound of embodiment 15 or 16, wherein R^A1 is H.

18. The compound of embodiment 15 or 16, wherein R^A1 is C1-3 alkyl, optionally methyl.

19. The compound of embodiment 1, 2 or 13, wherein ring

20. The compound of any preceding embodiment, wherein R¹ is R^lx.

21. The compound of any of embodiments 1 to 19, wherein R¹ is -Ci-3alkylene-R^lx.

22. The compound of any preceding embodiment, wherein R^lx is phenyl. 23. The compound of any of embodiments 1 to 21, wherein R^lx is a 5-6 membered heteroaryl, optionally a 5-6 membered heteroaryl containing 1 or 2 nitrogen atoms.

24. The compound of embodiment 23, wherein R^lx is pyridine or pyrazole.

25. The compound of embodiment 24, wherein R^lx is pyridine.

26. The compound of any of embodiments 1 to 21, wherein R^lx is a 5-6 membered saturated heterocycle.

27. The compound of embodiment 26, wherein R^lx is tetrahydropyran.

28. The compound of any of embodiments 1 to 21, wherein R^lx is a C3-4cycloalkyl, optionally cyclobutyl.

29. The compound of any preceding embodiment, wherein R^lx is substituted with 1 occurrence of R^ly.

30. The compound of embodiment 29, wherein the 1 occurrence of R^ly is selected from halo, Ci-shaloalkyl and Ci-3alkyl (e.g. fluoro, chloro, -CF3 and methyl).

31. The compound of any of embodiments 1 to 28, wherein R^lx is substituted with 2 occurrences of R^ly.

32. The compound of embodiment 31, wherein:

(i) both occurrences of R^ly are independently selected from halo, Ci-3haloalkyl and Ci-3alkyl (e.g. fluoro, chloro, -CF3 and methyl); or

(ii) one occurrence of R^ly is selected from halo, Ci-3haloalkyl, Ci-3alkyl, nitrile, Ci- shaloalkoxy and C3-4cycloalkoxy (e.g. fluoro, chloro, -CF3, methyl, nitrile, - OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy), and the second occurrence of R^ly is selected from halo, Ci-3haloalkyl and Ci-3alkyl e.g. (fluoro, chloro, -CF3 and methyl). 33. The compound of any of embodiments 1 to 28, wherein R^lx is substituted with 0 occurrences of R^ly.

34. The compound of any of embodiments 1 to 29 and 31, wherein each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-salkyl, nitrile, Ci-3alkoxy, Ci-shaloalkoxy and C3-4cycloalkoxy.

35. The compound of any of embodiments 1 to 29 and 31, wherein each R^ly is independently selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, C 1-3 haloalkoxy and C3- 4cycloalkoxy.

36. The compound of embodiment 35, wherein each R^ly is independently selected from halo, Ci-3haloalkyl and Ci-3alkyl.

37. The compound of embodiment 35, wherein each R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy.

38. The compound of embodiment 37, wherein each R^ly is independently selected from fluoro, chloro, -CF3 and methyl.

39. The compound of any of embodiments 1 to 19, wherein R¹ is Ci-3alkyl.

40. The compound of any of embodiments 1 to 19, wherein R¹ is Ci-3haloalkyl.

41. The compound of any of embodiments 1 to 19, wherein R¹ is phenyl.

42. The compound of embodiment 41, wherein R¹ is unsubstituted phenyl.

43. The compound of embodiment 41, wherein R¹ is phenyl substituted with 1 occurrence ofR^ly.

44. The compound of embodiment 43, wherein R¹ is 45. The compound of embodiment 41, 43 or 44, wherein R^ly is selected from halo, Ci- shaloalkyl and Ci-3alkyl (e.g. fluoro, chloro, -CF3 and methyl).

46. The compound of embodiment 41, wherein R¹ is phenyl substituted with 2 occurrences of R^ly.

The compound of embodiment 46, wherein

48. The compound of embodiment 46 or 47, wherein:

(i) both occurrences of R^ly are independently selected from halo, Ci-shaloalkyl and Ci-3alkyl (e.g. fluoro, chloro, -CF3 and methyl); or

(ii) one occurrence of R^ly is selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, Ci- shaloalkoxy and C3-4cycloalkoxy (e.g. fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy), and the second occurrence of R^ly is selected from halo, Ci-shaloalkyl and Ci-3alkyl e.g. (fluoro, chloro, -CF3 and methyl).

49. The compound of embodiment 46 or 47, wherein the 2 occurrences of R^ly are: i) halo and halo (e.g. F and F, or F and Cl), (ii) halo (e.g. F or Cl) and nitrile, or (iii) methyl and nitrile.

50. The compound of embodiment 49, wherein the 2 occurrences of R^ly are halo and halo (e.g. F and F, or F and Cl).

51. The compound of any of embodiments 1 to 19, wherein R¹ is pyridine.

52. The compound of embodiment 51, wherein R¹ is unsubstituted pyridine.

The compound of embodiment 52, wherein R¹ is 54. The compound of embodiment 52, wherein R¹ is

55. The compound of embodiment 51, wherein R¹ is pyridine substituted with 1 occurrence of R^ly.

56. The compound of embodiment 55, wherein R¹ is

57. The compound of embodiment 55, wherein

58. The compound of any of embodiments 55-57, wherein R^ly is selected from halo, Ci- shaloalkyl and Ci-3alkyl (e.g. fluoro, chloro, -CF3 and methyl).

59. The compound of embodiment 58, wherein R^ly is halo (e.g. fluoro) or Ci-3haloalkyl (e.g. -CF₃).

60. The compound of embodiment 51, wherein R¹ is pyridine substituted with 2 occurrences of R^ly.

61. The compound of embodiment 60, wherein R¹ is

62. The compound of embodiment 60 or 61, wherein:

(ii) one occurrence of R^ly is selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, Ci- shaloalkoxy and C3-4cycloalkoxy (e.g. fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy), and the second occurrence of R^ly is selected from halo, Ci-shaloalkyl and Ci-salkyl e.g. (fluoro, chloro, -CF3 and methyl).

63. The compound of any of embodiments 60-62, wherein each R^ly is halo (e.g. fluoro).

64. The compound of any preceding embodiment, wherein R² is selected from Ci- shaloalkoxy, C3-4cycloalkyl and halo.

65. The compound of embodiment 64, wherein R² is selected from C3-4cycloalkyl and halo.

66. The compound of embodiment 64, wherein R² is selected from -OCHF2, cyclopropyl and chloro.

67. The compound of embodiment 66, wherein R² is selected from cyclopropyl and chloro.

68. The compound of any preceding embodiment, wherein R³ is C3-4 alkyl substituted with one or two occurrences of hydroxyl, wherein one occurrence of the hydroxyl is at a tertiary carbon.

69. The compound of any preceding embodiment, wherein R³ is C3-4 alkyl substituted with two occurrences of hydroxyl, wherein one occurrence of the hydroxyl is at a tertiary carbon.

70. The compound of any preceding embodiment, wherein R is

71. The compound of any preceding embodiment, wherein R³ is

72. A compound which is a compound of Formula (II):

Formula (II) or a pharmaceutically acceptable salt thereof, wherein: ring A is: a) a 5-membered heteroaryl selected from pyrazole, imidazole and triazole, wherein ring A is optionally substituted with one occurrence of Ci-3alkyl or C2-4alkoxyalkyl, or

R² is selected from Ci-shaloalkoxy, C3-4cycloalkyl and halo.

73. The compound of embodiment 72, wherein the compound is a compound of Formula (II-A):

Formula (II-A) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R² are as defined in embodiment 72. 74. The compound of embodiment 72 or 73, wherein ring A is selected from pyrazole, imidazole and triazole, optionally substituted with one occurrence of Ci-3alkyl or C2- 4alkoxy alkyl.

75. The compound of embodiment 72 or 73, wherein ring A is selected from the following moi eties: wherein (R¹) indicates the point of attachment to R¹, and wherein R^A and R^Ax are each independently Ci-3alkyl or C2-4alkoxy alkyl.

76. The compound of embodiment 75, wherein R^A is Ci-3alkyl, optionally methyl.

77. The compound of embodiment 75, wherein R^Ax is Ci-3alkyl, optionally methyl or ethyl.

78. The compound of embodiment 75, wherein R^Ax is C2-4alkoxyalkyl, optionally - (CH₂)₂OCH3.

79. The compound of embodiment 72 or 73, wherein ring

80. The compound of any of embodiments 72 to 79, wherein R¹ is substituted with 1 occurrence of R^ly.

81. The compound of embodiment 80, wherein the 1 occurrence of R^ly is selected from halo, Ci-3haloalkyl and Ci-3alkyl (e.g. fluoro, chloro, -CF3 and methyl). 82. The compound of any of embodiments 72 to 79, wherein R¹ is substituted with 2 occurrences of R^ly.

83. The compound of embodiment 82, wherein:

(ii) one occurrence of R^ly is selected from halo, Ci-shaloalkyl, Ci-3alkyl, nitrile, Ci- shaloalkoxy and C3-4cycloalkoxy (e.g. fluoro, chloro, -CF3, methyl, nitrile, - OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy), and the second occurrence of R^ly is selected from halo, Ci-shaloalkyl and Ci-3alkyl e.g. (fluoro, chloro, -CF3 and methyl).

84. The compound of any of embodiments 72 to 80 or 82, wherein each R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy; optionally wherein each R^ly is independently selected from fluoro, chloro, -CF3 and methyl.

85. The compound of any of embodiments 72 to 79, wherein R¹ is substituted with 0 occurrences of R^ly.

86. The compound of any of embodiments 72 to 79 or 84, wherein R¹ is phenyl.

87. The compound of any of embodiments 72 to 79, wherein R¹ is unsubstituted phenyl.

88. The compound of any of embodiments 72 to 81 or 84, wherein R¹ is phenyl substituted with 1 occurrence ofR^ly.

89. The compound of embodiment 88, wherein R¹ is

90. The compound of any of embodiments 72 to 79 and 82 to 84, wherein R¹ is phenyl substituted with 2 occurrences of R^ly. The compound of embodiment 90, wherein R¹ is

92. The compound of embodiment 90 or 91, wherein the 2 occurrences of R^ly are: i) halo and halo (e.g. F and F, or F and Cl), (ii) halo (e.g. F or Cl) and nitrile, or (iii) methyl and nitrile.

93. The compound of embodiment 92, wherein the 2 occurrences of R^ly are halo and halo (e.g. F and F, or F and Cl).

94. The compound of any of embodiments 72 to 79 or 84, wherein R¹ is pyridine.

95. The compound of any of embodiments 72 to 79, wherein R¹ is unsubstituted pyridine.

96. The compound of embodiment 95, wherein R¹ is

98. The compound of any of embodiments 72 to 81 or 84, wherein R¹ is pyridine substituted with 1 occurrence ofR^ly.

99. The compound of embodiment 98, wherein R¹ is

100. The compound of embodiment 98, wherein 101. The compound of any of embodiments 98 to 100, wherein R^ly is halo (e.g. fluoro) or Ci-shaloalkyl (e.g. -CF3).

102. The compound of any of embodiments 72 to 79 and 82 to 84, wherein R¹ is pyridine substituted with 2 occurrences of R^ly. J

103. The compound of embodiment 102, wherein R¹ is ^{Rly N}

104. The compound of embodiment 102 or 103, wherein each R^ly is halo (e.g. fluoro).

105. The compound of any of embodiments 72 to 104, wherein R² is selected from C3- 4cycloalkyl and halo.

106. The compound of any of embodiments 72 to 104, wherein R² is selected from - OCHF2, cyclopropyl and chloro.

107. The compound of embodiment 106, wherein R² is selected from cyclopropyl and chloro.

108. The compound of any preceding embodiment, wherein one or more hydrogens present in the compound are deuterated.

109. The compound of any of embodiments 1-71, wherein the compound is a compound of Formula (I-tZ) or Formula (I-A-t/):

Formula (I-J) Formula (I-A-J) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹, R² and R³ are as defined in any of embodiments 1-71. 110. The compound of any of embodiments 72-107, wherein the compound is a compound of Formula (Il-tZ) or Formula (II-A-t/):

Formula (II-J) Formula (II-A-J) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R² are as defined in any of embodiments 72-107.

111. A compound which is a compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.

112. The compound of any preceding embodiment, wherein the compound is a pharmaceutically acceptable salt.

113. The compound of any of embodiments 1-111, wherein the compound is a non-salt form.

114. A composition comprising the compound of any one of embodiments 1 to 113.

115. The composition of embodiment 114, further comprising a pharmaceutically acceptable excipient.

116. A method of inhibiting activity of Transient Receptor Potential Vanilloid 4 (TRPV4), comprising contacting TRPV4 with the compound of any one of embodiments 1 to 113 or the composition of embodiment 114 or 115.

117. The method of embodiment 116, wherein the method is performed in vivo.

118. The method of embodiment 116, wherein the method is performed in vitro. 119. A method of inhibiting activity of TRPV4 in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of any one of embodiments 1 to 113 or the composition of embodiment 114 or 115 to the subject.

120. A compound of any of embodiments 1 to 113 or a composition of embodiment 114 or 115 for use in therapy.

121. A method of treating or preventing a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of any one of 1 to 113 or the composition of embodiment 114 or 115.

122. A method of treating a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of any one of 1 to 113 or the composition of embodiment 114 or 115.

123. A compound of any of embodiments 1 to 113 or a composition of embodiment 114 or 115 for use in a method of treating or preventing a TRPV4-associated disease or disorder.

124. A compound of any of embodiments 1 to 113 or a composition of embodiment 114 or 115 for use in a method of treating a TRPV4-associated disease or disorder.

125. Use of a compound of any of embodiments 1 to 113 in the manufacture of a medicament for treating or preventing a TRPV4-associated disease or disorder.

126. Use of a compound of any of embodiments 1 to 113 in the manufacture of a medicament for treating a TRPV4-associated disease or disorder.

127. The method of embodiment 121 or 122, the compound or composition for use of embodiment 123 or 124 or the use of embodiment 125 or 126, wherein the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, cancer, a genetic disease or disorder, pain, or combination thereof. 128. The method of embodiment 121 or 122, the compound or composition for use of embodiment 123 or 124 or the use of embodiment 125 or 126, wherein the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, or combination thereof.

129. The method of embodiment 121 or 122, the compound or composition for use of embodiment 123 or 124 or the use of embodiment 125 or 126, wherein the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, neuropathic pain, chronic vulvar pain, colitis, sclerosis, obesity, diabetes, lung ischemia reperfusion injury, cystic fibrosis, or combination thereof.

130. The method of embodiment 121 or 122, the compound or composition for use of embodiment 123 or 124 or the use of embodiment 125 or 126, wherein the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuro-psychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, colitis, sclerosis, obesity, diabetes, or combination thereof.

131. The method of embodiment 121 or 122, the compound or composition for use of embodiment 123 or 124 or the use of embodiment 125 or 126, wherein the TRPV4-associated disease or disorder is cancer. 132. The method, compound or composition for use, or the use of embodiment 131, wherein the cancer is hepatocellular carcinoma, colon cancer, colorectal cancer or non-small cell lung cancer.

133. The method, compound or composition for use, or the use of embodiment 131, wherein the cancer is hepatocellular carcinoma or colorectal cancer.

134. The method of embodiment 121 or 122, the compound or composition for use of embodiment 123 or 124 or the use of embodiment 125 or 126, wherein the TRPV4-associated disease or disorder is a cardiovascular disease or disorder.

135. The method, compound or composition for use, or the use of embodiment 134, wherein the cardiovascular disease or disorder is hypertrophic cardiomyopathy.

EXAMPLES

The specific examples included herein are for illustrative purposes only and are not to be considered as limiting to this disclosure. These examples provide guidance to the skilled person in the art to prepare and use the compounds, compositions, and methods of the present disclosure. Moreover, the compounds, compositions, and methods provided herein have been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration. It will be apparent to those skilled in the art that the disclosure is susceptible to additional embodiments and that certain of the details described herein may be varied without departing from the basic principles of the disclosure.

In the following Examples, chemical shifts are expressed as parts per million (ppm) units. Coupling constants (J), where accounted for, are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m, (multiplet), br (broad). Column chromatography was performed on silica gel unless otherwise stated. The naming program used is ACD/Chem Sketch 2020.2.0. Vibrational circular dichroism was used for some examples to indicate absolute configuration.

Table 2 shows a list of intermediates used in the following Examples.

Table 2. Intermediates

Preparation of Intermediates 1-102 is described below.

Intermediate 1: (25)-2-[(35)-piperidin-3-yl]propane-l,2-diol

Step 1 : 1-benzyl 3-ethyl (35)-piperidine-l,3-dicarboxylate

To a solution of ethyl (S)-piperidine-3-carboxylate (50 g, 318.04 mmol) in water (497 mL) and THF (497 mL) was added sodium bicarbonate (53.4 g, 636.08 mmol) and N- (Benzyl oxy carbonyloxy)succinimide (95 g, 381.65 mmol) in portions at 0 °C. The resulting reaction mixture was left to slowly reach room temperature and stirred for 16 h. The reaction mixture was then diluted with EtOAc (1 L) and water (500 mL). After extraction, the organic phase was further washed with water (2x200 mL) and brine (200 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 105 g of crude. This crude was purified by prep-HPLC: Column: DCPakA, 250x50 mm, 5 microm, 2% IPA in CO2 120 bar, 400 mL/min to obtain the title compound (79 g, 85 %): 1H NMR (500 MHz, DMSOd6, 25°C) 5 1.15 (3H, d), 1.39 (1H, d), 1.63 (2H, dtd), 1.90 (1H, s), 2.47 (1H, s), 2.93- 3.27 (2H, m), 3.6-3.8 (1H, m), 3.94 (1H, d), 4.05 (2H, d), 5.07 (2H, d), 7.28-7.41 (5H, m).

Step 2: (35)-l-[(benzyloxy)carbonyl]piperidine-3-carboxylic acid

To a solution of 1-benzyl 3-ethyl (S)-piperidine-l,3-dicarboxylate (79 g, 271.15 mmol) in THF (1356 ml) and water (226 ml) was added dropwise a solution of lithium hydroxide monohydrate (12.52 g, 298.27 mmol) in water (226 ml) during 10 min at 0 °C. Cooling was removed and after stirring 3 hours at rt, the reaction mixture was quenched by the addition of 5M aqueous HC1 solution to reach pH ~4. The mixture was then extracted with EtOAc (1.5 L) and the organic phase was washed with water (2x300 mL) and brine (400 mL). After drying over anhydrous MgSO4 and filtration, the organic phase was evaporated to obtain (S)-l- ((benzyloxy)carbonyl)piperidine-3-carboxylic acid (71.0 g, 99 %): 1H NMR (500 MHz, DMSO, 25°C) 5 1.3-1.42 (1H, m), 1.49-1.57 (1H, m), 1.58-1.68 (1H, m), 1.86-1.96 (1H, m), 2.29-2.41 (1H, m), 2.8-3.2 (2H, m), 3.68-3.86 (1H, m), 3.91-4.09 (1H, m), 5.07 (2H, s), 7.28-7.41 (5H, m), 12.42 (1H, s). This material was used in the next step without further purification.

Step 3: benzyl (35)-3-[methoxy(methyl)carbamoyl]piperidine-l-carboxylate

To a solution of (S)-l-((benzyloxy)carbonyl)piperidine-3 -carboxylic acid (71 g, 269.66 mmol) in dichloromethane (1269 ml) was added at 0 °C N,O-dimethylhydroxylamine hydrochloride (28.9 g, 296.63 mmol) and 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3- tetramethylisouronium hexafluorophosphate(V) (113 g, 296.63 mmol). Then, triethylamine (79 ml, 566.29 mmol) was added over a period of 10 minutes. The mixture was stirred 1.5 h at 0 °C followed by 1.5 h at room temperature. The reaction mixture was then quenched by the addition of water (300 mL) followed by a vigorous stirring for 10 minutes. After further dilution with water (400 mL) and phases separation, the organic phase was washed with water (2x400 mL) and brine (400 mL). The organic phase was dried over MgSO4, filtered and evaporated to obtain 135 g of crude. This crude was divided in three parts and purified by flash chromatography (Biotage, 340 g column KP-Sil, 10% EtOAc in heptane (1CV) to 80% (8CV)) to yield the title compound (72.0 g, 87 %, contains 5 wt-% tetramethyl urea): 1H NMR (500 MHz, DMSO, 25°C) 5 1.34-1.46 (1H, m), 1.48-1.6 (1H, m), 1.63-1.73 (1H, m), 1.79-1.85 (1H, m), 2.72-2.98 (3H, m), 3.07 (3H, s), 3.53-3.74 (3H, m), 3.89-3.96 (1H, m), 3.96-4.05 (1H, m), 5.05 (1H, d), 5.10 (1H, d), 7.28-7.41 (5H, m).

Step 4: benzyl (35)-3-acetylpiperidine-l-carboxylate

To a solution of benzyl (S)-3-(methoxy(methyl)carbamoyl)piperidine-l -carboxylate (72 g, 235.02 mmol) in dry THF (689 ml) at -10 °C was added dropwise a 3M solution methylmagnesium bromide in Et2O (94 ml, 282.02 mmol) over 40 minutes. The reaction mixture was left to slowly reach room temperature. Then, after 1 hour, the reaction mixture was cooled to 0 °C and quenched by the careful addition of 5% aqueous HC1 solution until the reaction mixture reached pH ~4. The mixture was diluted with TBME (1 L) and water (200 mL) and extracted. The organic phase was further washed with water (200 mL) and brine (200 mL). The organic phase was dried over MgSO4, filtered and evaporated to obtain crude title compound that was used in the next step without further purification (58.6 g, 95 %): 1H NMR (500 MHz, CDC13, 25°C) 5 1.42-1.6 (2H, m), 1.69-1.81 (1H, m), 1.95-2.04 (1H, m), 2.17 (3H, s), 2.43-2.61 (1H, m), 2.82-2.91 (1H, m), 2.94-3.06 (1H, m), 3.92-4.08 (1H, m), 4.12-4.31 (1H, m), 5.11 (1H, d), 5.15 (1H, d), 7.28-7.4 (5H, m).

Step 5: benzyl (3A)-3-(prop-l-en-2-yl)piperidine-l-carboxylate

In a 5 L reactor equipped with mechanical stirring was added dry THF (2069 ml) and methyltriphenylphosphonium bromide (112 g, 314.00 mmol). The suspension was cooled to 10 °C followed by dropwise addition of 1.6M in hexanes of BuLi (182 ml, 291.57 mmol), while maintaining the internal temperature between 11-14 °C. After 50 minutes stirring the internal temperature reached 6 °C and a solution of benzyl (S)-3 -acetylpiperidine- 1- carboxylate (58.61 g, 224.28 mmol) in dry THF (552 ml) was added over a period of 1 hour while maintaining the internal temperature at <8 °C. After an additional 1 hour, the reaction mixture was carefully quenched by the addition of saturated NH4C1 solution (1 L) followed by TBME (1 L). After vigorous stirring for 10 minutes, the water phase was separated and the organic phase washed with brine (1 L). The organic phase was dried over MgSO4, filtered and evaporated to obtain a crude solid. This solid was suspended in diethyl ether (400 mL). The white solid of triphenylphosphine oxide was filtered off and washed with diethyl ether (3x50 mL). The filtrate was evaporated to -1/2V and the resulting solution kept at 5 °C for 60 hours. The formed crystals of triphenylphosphine oxide were filtered off and washed with diethyl ether (3x50 mL). The filtrate was evaporated to obtain 68.6 g of crude. This crude was divided in two equal parts and purified by flash chromatography (Biotage, KP-SIL 340 g, 5% EtOAc in Heptane (2CV) then to 30% (6 CV)). The same column was used in the second purification after washing it with 100% EtOAc and equilibration to 5% EtOAc. The fractions containing product of each purifications were combined and evaporated to yield the title compound (48.2 g, 83 %): 1H NMR (500 MHz, CDC13, 25°C) 5 1.3-1.4 (1H, m), 1.43-1.55 (1H, m), 1.66-1.79 (4H, m), 1.85-1.94 (1H, m), 1.99-2.1 (1H, m), 2.52-2.67 (1H, m), 2.67- 2.78 (1H, m), 4.07-4.36 (2H, m), 4.72 (1H, s), 4.79 (1H, s), 5.14 (2H, s), 7.28-7.39 (5H, m). A separate batch (63 g) prepared under less controlled conditions resulted in a product having partial racemization and was resolved by preparative chiral chromatography (Column: (R, R)- WHELK-O®l-Kromasil, 5*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.5% 2M NH3-MeOH)-HPLC; Flow rate: 200 mL/min; Gradient: isocratic 25% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 9.5; RT2(min): 10.60; Sample Solvent: MeOH-HPLC; Injection Volume: 9.9 mL; Number Of Runs: 71). Concentration of the appropriate fractions gave benzyl (3R)-3-(prop-l-en-2- yl)piperidine-l -carboxyl ate (50.9 g, 82 %) and benzyl (3R)-3-(prop-l-en-2-yl)piperidine-l- carb oxy late (0.7 g, 1.1%).

Step 6: benzyl (35)-3-[(2A5)-l,2-dihydroxypropan-2-yl]piperidine-l-carboxylate

[0183] To a stirred solution of benzyl (R)-3 -(prop- l-en-2-yl)piperidine-l -carboxylate (24.12 g, 93.00 mmol) in THF (698 ml) and water (233 ml) was added at room temperature 4- methylmorpholine-4-oxide (11.98 g, 102.30 mmol) and potassium dioxidodioxoosmium dihydrate (1.713 g, 4.65 mmol). After 23 hours, additional 4-methylmorpholine-4-oxide was added (1.1 g, 0.1 equiv.) and stirring was continued for 24 h. The reaction mixture was then diluted with EtOAc (I L) and washed with saturated NH4C1 solution (3x400 mL) and brine (400 mL). The organic phase was dried over MgSO4, filtered and evaporated to obtain 27.61 g of crude. This crude was purified by flash chromatography (Biotage, 340 g silica gel KP- SIL, 50% EtOAc (2CV), 50 to 100% EtOAc (10 CV) in Heptane) to yield the title compound as a mixture of diastereomers (22.25 g, 82 %): 1H NMR (500 MHz, DMSOd6, 25°C) 5 0.9- 1.02 (3H, m), 1.08-1.32 (2H, m), 1.4-1.83 (3H, m), 2.5-2.7 (2H, m), 3.1-3.26 (2H, m), 3.93- 3.99 (1H, m), 4.07 (1H, s), 4.1-4.23 (1H, m), 4.46-4.52 (1H, m), 4.99-5.09 (2H, m), 7.25- 7.38 (5H, m).

Step 7: benzyl (35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidine-l-carboxylate and benzyl (35)-3-[(2A)-l,2-dihydroxypropan-2-yl]piperidine-l-carboxylate

[0185] 44.5 g of a mixture of diastereoisomers were separated (Column: Chiralpak® IA, 250x50 mm, 5 micron, 17% EtOH/DEA 100/20 mM in CO2, 120 bar) to obtain the major product, benzyl (3S)-3-[(2S)-l,2-dihydroxypropan-2-yl]piperidine-l-carboxylate (23.62 g, 52 %): 1H NMR (500 MHz, DMSOd6, 25°C) 5 0.93 (3H, s), 1.11-1.2 (1H, m), 1.2-1.31 (1H, m), 1.44-1.55 (1H, m), 1.59-1.66 (1H, m), 1.7-1.76 (1H, m), 2.5-2.72 (2H, m), 3.21 (2H, d), 3.94-4.01 (1H, m), 4.08 (1H, s), 4.17-4.23 (1H, m), 4.49 (1H, t), 5.03 (1H, d), 5.06 (1H, d), 7.25-7.38 (5H, m), Chiral HPLC: 99.5% d.e.; and the minor product benzyl (3S)-3-[(2R)-l,2- dihydroxypropan-2-yl]piperidine-l -carboxylate (16.74 g, 38 %): 1H NMR (500 MHz, DMSOd6, 25 °C) 5 0.99 (3H, s), 1.18-1.3 (2H, m), 1.4-1.51 (1H, m), 1.6-1.67 (1H, m), 1.77- 1.82 (1H, m), 2.5-2.68 (2H, m), 3.1-3.17 (1H, m), 3.23-3.29 (1H, m), 3.93-4 (1H, m), 4.08 (1H, s), 4.1-4.18 (1H, m), 4.50 (1H, t), 5.04 (2H, s), 7.25-7.38 (5H, m). Chiral HPLC: 91.9% d.e. Absolute stereochemistry determined by vibrational circular dichroism (VCD).

[0186] Step 8: (25)-2-[(35)-piperidin-3-yl]propane-l,2-diol (Intermediate 1)

[0187] To palladium on carbon (0.508 g, 0.24 mmol) placed in autoclave reactor and in MeOH (5 mL) was added a solution of benzyl (S)-3-((S)-l,2-dihydroxypropan-2- yl)piperidine-l -carboxyl ate (5 g, 17.04 mmol) in MeOH (48.7 mL) The mixture was sealed in the reactor, purged with N2 five times, with H2 five times and left over the weekend stirring at room temperature under 2 bars of H2. After 68 hours and once the mixture was purged with N2, the suspension was filtered through a pad of celite. The solid in the filter was washed with MeOH (3x50 mL) and the resulting filtrate evaporated to yield (S)-2-((S)-piperidin-3- yl)propane-l,2-diol (2.75 g, Quantitative yield). 1H NMR (500 MHz, D2O) 1.10 (3H, s), 1.23 - 1.35 (1H, m), 1.49 - 1.62 (1H, m), 1.79 - 1.89 (3H, m), 2.58 - 2.7 (2H, m), 3.13 - 3.19 (1H, m), 3.27 - 3.33 (1H, m), 3.45 (1H, d), 3.55 (1H, d). 3 H’s exchanged with D.

Intermediate 2 : (2S)-2- {(35)- 1- [(4-azido-2-chlor ophenyl)methyl] piperidin-3-yl} pr opane- 1,2-diol

Step 1 : tert-butyl (3-chloro-4-formylphenyl)carbamate

Cl O T I] BocHN^^^

To a mixture of Xantphos (1.32 g, 2.28 mmol), Xantphos Pd G3 (2.16 g, 2.28 mmol), 4- bromo-2-chlorobenzaldehyde (2.50 g, 11.39 mmol) and tert-butyl carbamate (1.60 g, 13.7 mmol) in 1,4-dioxane (20 mL) under nitrogen was added cesium carbonate (7.42 g, 22.78 mmol), then stirred at 90 °C for 2 hours. The resulting mixture was filtered through celite, combined with an identical batch and concentrated. The residue was purified by C18-flash chromatography, elution gradient 0 to 80 % acetonitrile in water. Appropriate fractions were concentrated to afford the title compound as a yellow solid (4.10 g, 82%): 1H NMR (400 MHz, DMSO-d6) 5 1.49 (s, 9H), 7.51 (dd, J = 8.7, 2.0 Hz, 1H), 7.74-7.81 (m, 2H), 10.09 (s, 1H), 10.17 (s, 1H). m/z (ES+) [M+H]⁺ = 256.

Step 2: tert-butyl [3-chloro-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-l- yl}methyl)phenyl]carbamate

To a mixture of tert-butyl (3-chloro-4-formylphenyl)carbamate (2.00 g, 7.82 mmol), sodium cyanoborohydride (0.98 g, 15.6 mmol) and intermediate 1 (1.87 g, 11.7 mmol) in methanol (30 mL) was added acetic acid (0.90 mL, 15.6 mmol), then stirred at rt for 2 hours. The residue was purified by C18-flash chromatography, elution gradient 0 to 80 % acetonitrile in water. Appropriate fractions were concentrated to afford the title compound as a yellow solid (1.44 g, 46%): 1H NMR (400 MHz, DMSO-d6) 5 0.96 (s, 3H), 1.18 (s, 1H), 1.48 (s, 9H), 1.55-1.72 (m, 2H), 1.73-1.99 (m, 2H), 2.85-2.93 (m, 1H), 3.48 (d, J = 11.9 Hz, 1H), 4.3-4.44 (m, 3H), 4.75 (s, 1H), 7.45 (d, 1H), 7.57 (d, 1H), 7.73 (d, J = 2.1 Hz, 1H), 9.79 (s, 1H). m/z (ES+) [M+H]⁺ = 399.

Step 3: (25)-2-{(35)-l-[(4-amino-2-chlorophenyl)methyl]piperidin-3-yl}propane-l,2-diol

Trifluoroacetic acid (3 mL, 38.9 mmol) was added to tert-butyl [3-chloro-4-({(35)-3-[(25)- l,2-dihydroxypropan-2-yl]piperidin-l-yl}methyl)phenyl]carbamate (1.38 g, 3.46 mmol) in dichloromethane (14 mL), then stirred for 1 hour and concentrated. The residue was purified by C18-flash chromatography, elution gradient 0 to 80 % acetonitrile in water. Appropriate fractions were concentrated to afford the title compound as a colourless oil (0.90 g, 87 %): 1H NMR (400 MHz, DMSO-d6) 5 0.95 (s, 3H), 1.14 (d, J = 12.7 Hz, 1H), 1.54-1.69 (m, 2H), 1.76-1.98 (m, 2H), 2.80 (q, J = 11.6 Hz, 2H), 3.05-3.18 (m, 1H), 3.20 (s, 2H), 3.29 (d, J = 12.0 Hz, 1H), 3.46 (d, J = 11.8 Hz, 1H), 4.21 (d, J = 4.8 Hz, 2H), 6.51-6.57 (m, 1H), 6.67 (d,

J = 2.3 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H). m/z (ES+) [M+H]⁺ = 299.

Step 4: (25)-2-{(35)-l-[(4-azido-2-chlorophenyl)methyl]piperidin-3-yl}propane-l,2-diol

(25)-2-{(35)-l-[(4-amino-2-chlorophenyl)methyl]piperidin-3-yl}propane-l,2-diol (520 mg, 1.74 mmol) was added to acetonitrile (1 mL), cooled to 0 °C, then w-Butylnitrite (269 mg, 2.61 mmol) and trimethylsilyl azide (241 mg, 2.09 mmol) was added slowly at 0 °C . The resulting solution was stirred at RT for 2 hours. The reaction mixture was then applied onto a silica column followed by flash chromatography using stepwise gradient elution (0-30 % methanol in dichloromethane). Appropriate fractions were concentrated to afford the title compound as a white solid (0.34 g, 60 %): 1H NMR (400 MHz, DMSO-d6, 26°C) 5 0.94 (4H, d), 1.06-1.2 (1H, m), 1.38-1.58 (1H, m), 1.64-2.02 (4H, m), 2.15-2.38 (1H, m), 3.11-3.23 (3H, m), 3.34 (1H, s), 4.25 (2H, s), 4.66 (1H, t), 7.24 (2H, d), 7.64 (1H, s). m/z (ES+) [M+H]⁺ = 325.

Intermediate 3: 4-ethynyl-3-methylbenzonitrile

Step 1 : 3-methyl-4-[(trimethylsilyl)ethynyl]benzonitrile

To a stirred mixture of copper(I) iodide (48.6 mg, 0.26 mmol), ethynyltrimethylsilane (301 mg, 3.06 mmol) , diisopropylamine (774 mg, 7.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (295 mg, 0.26 mmol) in toluene (6 mL) under nitrogen was added 4-bromo-3 -methylbenzonitrile (500 mg, 2.55 mmol), then stirred at rt for 15 h. The reaction mixture was then applied onto a silica column followed by flash chromatography using stepwise gradient elution (0-30 % ethyl acetate in petroleum ether).

Appropriate fractions were concentrated to afford the title compound as a colourless oil (430 mg, 79 %): 1H NMR (400 MHz, DMSO-d6, 23°C) 5 0.25 (9H, s), 2.39 (3H, s), 7.56 (1H, d), 7.59-7.65 (1H, m), 7.78 (1H, dt). m/z (ES+) [M+H]⁺ = 214.

Step 2: 4-ethynyl-3 -methylbenzonitrile

To a stirred mixture of potassium carbonate (295 mg, 2.14 mmol) in 1 : 1 THF-methanol (4 mL) was added 3-methyl-4-[(trimethylsilyl)ethynyl]benzonitrile (380 mg, 1.78 mmol), then stirred at rt for 15 h. The reaction mixture was then applied onto a silica column followed by flash chromatography using stepwise gradient elution (0-70 % ethyl acetate in petroleum ether). Appropriate fractions were concentrated to afford the title compound as a white solid (183 mg, 73 %): 1H NMR (400 MHz, DMSO-d6, 23°C) 5 2.41 (3H, s), 4.77 (1H, s), 7.61 (1H, d), 7.67 (1H, dd), 7.80 (1H, dt).

Intermediate 4 (25)-2-[(35)-l-{[4-azido-2-(difluoromethoxy)phenyl]methyl}piperidin-3- yl]propane-l,2-diol

Step . tert-butyl [3-(difluoromethoxy)-4-formylphenyl]carbamate

XantPhos Pd G3 (151 mg, 0.16 mmol) was added to 4-bromo-2- (difluoromethoxy)benzaldehyde (200 mg, 0.80 mmol) and cesium carbonate (260 mg, 0.80 mmol) in 1,4-di oxane (4.5 mL) at RT under nitrogen. The resulting mixture was stirred at 90 °C for 4 hours. The reaction mixture was then diluted with EtOAc (50 mL), and washed sequentially with water (2 x 50 mL) brine (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using EtOAc in petroleum ether (20-30 %, gradient elution) followed by concentration of the appropriate fraction gave the title compound as a yellow solid (0.100 g, 44 %): 'H NMR (300 MHz, DMSO-d6) 5 10.09 (d, J = 9.7 Hz, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.54 - 7.03 (m, 2H), 1.50 (s, 9H).

Step 2'. tert-butyl [3-(difluoromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-

1 -yl }methyl)phenyl]carbamate

Intermediate 1 (1.663 g, 10.44 mmol) was added to tert-butyl [3-(difluoromethoxy)-4- formylphenyl]carbamate (3g, 10.44 mmol) in DCE (30mL) over a period of 10 minutes, then added sodium triacetoxyborohydride (6.64 g, 31.33 mmol). The resulting mixture was stirred at 25 °C for 12 hours, then concentrated. Flash Cl 8- chromatography using acetonitrile in water (0-50 %, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a brown solid (3.00 g, 67 %): 'H NMR (300 MHz, DMSO, 22°C) 5 0.94 (s, 3H), 1.16 (q, J = 15.3, 13.5 Hz, 1H), 1.47 (s, 9H), 1.58 (d, J = 13.3 Hz, 1H), 1.68 (d, J = 13.2 Hz, 1H), 1.89 (dt, J = 27.1, 13.3 Hz, 2H), 2.69-2.88 (m, 2H), 3.15 (s, 1H), 3.27 (d, J = 11.8 Hz, 1H), 3.45 (d, J = 12.0 Hz, 1H), 4.21 (d, J = 4.5 Hz, 2H), 7.06 (d, J = 73.1 Hz, 1H), 7.29 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.57 (s, 1H), 9.27 (s, 1H), 9.77 (s, 1H).

Step 3: (25)-2-[(35)-l-{[4-amino-2-(difluoromethoxy)phenyl]methyl}piperidin-3-yl]propane- 1,2-diol tert-butyl [3-(difluoromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-l- yl}methyl)phenyl]carbamate (lOOmg, 0.23 mmol) in DCM (2 mL), TFA (0.4mL) . The resulting mixture was stirred at 25 °C for 2 hours, then concentrated. Flash C18 chromatography of the residue using acetonitrile in water (0-100 %, gradient elution), followed by concentration of the appropriate fractions gave the title compound as a white solid (0.049 g, 64 %): ¹ H NMR (300 MHz, DMSO-d6) 5 7.28 - 6.62 (m, 2H), 6.52 - 6.30 (m, 2H), 5.30 (s, 2H), 4.42 (s, 1H), 3.97 (s, 1H), 3.18 (d, 2H), 2.91 (d, 1H), 2.73 (s, 1H), 1.80 (s, 2H), 1.61 (d, 3H), 1.48 - 1.17 (m, 1H), 0.91 (s, 4H).

Step 4: (25)-2-[(35)-l-{ [4-azido-2-(difluoromethoxy)phenyl]methyl}piperidin-3-yl]propane- 1 ,2-diol (Intermediate 4)

(25)-2-[(35)-l-{[4-amino-2-(difluoromethoxy)phenyl]methyl}piperidin-3-yl]propane-l,2-diol (550 mg, 1.66 mmol) was added to acetonitrile (6 mL) cooled to 0°C, then added n- butylnitrite (258 mg, 2.50 mmol) and trimethylsilyl azide (230 mg, 2.00 mmol) slowly at 0 °C. The resulting solution was stirred at RT for 2 hours, then concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-70 %) followed by concentration of the appropriate fraction gave the title compound as a yellow solid (500 mg, 84%): 1H NMR (400 MHz, DMSO-d6, 26°C) 5 0.95 (6H, s), 1.18 (2H, s), 1.60 (3H, s), 1.69 (2H, d), 1.83 (2H, s), 1.94 (2H, s), 2.85 (4H, s), 3.21 (4H, d), 3.47 (2H, s), 4.30 (3H, s), 4.35-4.4 (2H, m), 4.72 (2H, s), 7.02 (2H, s), 7.16 (3H, s), 7.37 (1H, s), 7.56 (1H, s), 7.66 (2H, s), 9.41 (2H, s). m/z (ES+) [M+H]⁺ = 357.

Intermediate 5, (25)-2-{(35)-l-[(4-azido-2-cyclopropylphenyl)methyl]piperidin-3- yl}propane-l,2-diol

Step . 4-bromo-2-cyclopropylbenzoic acid

Diacetoxypalladium (0.457 g, 2.03 mmol) was added to a solution of 4-bromo-2 -iodobenzoic acid (13.3 g, 40.68 mmol), cyclopropylboronic acid (4.19 g, 48.82 mmol), potassium phosphate (30.2 g, 142.39 mmol) and tricyclohexylphosphonium tetrafluoroborate (1.648 g, 4.48 mmol) in 4: 1 toluene-water (200 mL) under nitrogen. The resulting reaction mixture is stirred at 100 °C overnight. The reaction mixture was then allowed to cool to rt and poured in water and extracted with EtOAc. The aqueous phase is acidified to pH 2 with 1 M HC1, and extracted with EtOAc twice. The combined organic phases were washed with brine, dried (MgSCh), filtered and concentrated. The remaining residue was purified by column chromatography on silica gel (0-30% EtOAc in Heptanes) to yield the title compound as a beige solid (6.11 g, 62.3 %): ¹ H NMR (500 MHz, CDC13) 0.7 - 0.78 (2H, m), 1.03 - 1.12 (2H, m), 2.74 - 2.84 (1H, m), 7.18 (1H, d), 7.38 (1H, dd), 7.85 (1H, d).

Step 2: (4-bromo-2-cyclopropylphenyl)methanol

Borane dimethyl sulfide complex solution (4.81 ml, 50.69 mmol) was added dropwise to a solution of 4-bromo-2-cyclopropylbenzoic acid (6.11 g, 25.34 mmol) at room temperature and stirred overnight. The reaction mixture was quenched with IM HC1, diluted with CH2C12 and passed through a phase separator. The organic phase was concentrated and column chromatography of the residue using EtOAc in heptane (0-50%, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound which crystallized upon standing (5.39 g, 94 %, light yellow solid): 'H NMR (500 MHz, CDC13) 0.65 - 0.71 (2H, m), 0.93 - 1.03 (2H, m), 1.93 - 2.02 (1H, m), 4.83 (2H, s), 7.13 (1H, d), 7.21 - 7.28 (1H, m), 7.32 (1H, dd).

Step 3: 4-bromo-2-cyclopropylbenzaldehyde

DMSO (1.062 mL, 14.96 mmol) was slowly added to a cold solution (-78°C, acetone/cardice) of oxalyl di chloride (0.636 mL, 7.41 mmol) in di chloromethane (40 mL). After stirring for 5 minutes, (4-bromo-2-cyclopropylphenyl)methanol (1.02 g, 4.49 mmol) was added as a solution in di chloromethane (10 mL), and a thick suspension formed. After stirring for a further 15 minutes, triethylamine (4.16 mL, 29.91 mmol) was added and the thick colorless suspension was allowed to slowly warm to rt overnight. The reaction was quenched with water (50 mL) and acidified with aq. 1.0M HC1 (50 mL). The organic phase was isolated by passing through a phase separator, then concentrated which gave a colorless oil, which slowly crystallised to give a mixture of solid and colourless oil. The residue was purified by automated flash column chromatography (Biotage Selekt) via a Biotage® Sfar Silica HC D 25 g/20 pm column, preconditioned with heptane. The product was isolated by isocratic elution with heptane (2CV) followed by gradient elution 0 to 20% EtOAc in heptane over 15CV, to afford colorless oil (770 mg, 76%): 'H NMR (500 MHz, CDC13, 25°C) 5 0.77-0.83 (2H, m), 1.07-1.16 (2H, m), 2.55-2.64 (1H, m), 7.27 (1H, d), 7.46 (1H, dd), 7.67 (1H, d), 10.54 (1H, s).

Step 4: tert-butyl (3-cyclopropyl-4-formylphenyl)carbamate

Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (1.84 g, 1.78 mmol) was added to a mixture of xantphos (1.54 g, 2.67 mmol), cesium carbonate (5.79 g, 17.77 mmol), 4- bromo-2-cyclopropylbenzaldehyde (2 g, 8.89 mmol) and tert-butyl carbamate (2.08 g, 17.8 mmol) in 1,4-dioxane (15 mL) under nitrogen. The resulting reaction mixture was stirred at 90 °C for 14 hours, then filtered through a plug of silica and concentrated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (with 0.1%FA), followed by concentration. The residue was further purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in petroleum ether. Appropriate fractions were concentrated to provide the title compound as a colourless oil (0.700 g, 30.1 %): 1H NMR (300 MHz, DMSO-d6, 24°C) 5 0.63-0.7 (m, 2H), 0.98-1.06 (m, 2H), 1.48 (s, 9H), 2.71-2.82 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 9.72 (s, 1H), 10.31 (s, 1H). m/z (ES+) [M+H]⁺ = 262.

Step 5: tert-butyl [3-cyclopropyl-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-l- yl}methyl)phenyl]carbamate

Sodium cyanoborohydride (481 mg, 7.65 mmol) was added to tert-butyl (3-cyclopropyl-4- formylphenyl)carbamate (500 mg, 1.91 mmol), intermediate 1 (396 mg, 2.49 mmol) and acetic acid (115 mg, 1.91 mmol) in MeOH (8 mL). The resulting mixture was stirred at RT for 2 days, then concentrated. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (with 0.1% formic acid). Appropriate fractions were concentrated to afford the title compound as a yellow solid (760 mg, 98 %): 1H NMR (300 MHz, MeOD, 20°C) 5 0.71-0.81 (m, 2H), 1.03-1.09 (m, 2H), 1.09 (s, 3H), 1.28-1.41 (m, 1H), 1.51 (s, 9H), 1.72-1.93 (m, 2H), 2.01 (d, J = 10.3 Hz, 1H), 2.05- 2.13 (m, 2H), 2.9-3.04 (m, 2H), 3.37-3.57 (m, 3H), 3.70 (d, J = 12.7 Hz, 1H), 4.48 (s, 2H), 7.15 (s, 1H), 7.36 (d, J = 1.2 Hz, 2H). m/z (ES+) [M+H]⁺ = 405.

Step 6: (25)-2-{(35)-l-[(4-amino-2-cyclopropylphenyl)methyl]piperidin-3-yl}propane-l,2- diol

Hydrochloric acid (1.85 mL, 7.42 mmol) was added to tert-butyl [3-cyclopropyl-4-({(35 -3- [(25)-l,2-dihydroxypropan-2-yl]piperidin-l-yl}methyl)phenyl]carbamate (750 mg, 1.85 mmol) in 1,4-di oxane (2 mL) . The resulting mixture was stirred at RT for overnight, then purified by flash C18-flash chromatography, elution gradient 0 to 100% MeCN in water (with 0.1% ammonia). Appropriate fractions were concentrated to afford the title compound as a brown oil (330 mg, 58.5 %): 1H NMR (300 MHz, DMSO, 21°C) 5 0.44-0.56 (m, 2H), 0.77- 0.88 (m, 2H), 0.91 (s, 3H), 1.01 (d, J = 12.2 Hz, 1H), 1.23 (s, 1H), 1.35 (d, J = 12.8 Hz, 1H), 1.61 (d, J = 11.3 Hz, 3H), 1.78 (d, J = 14.8 Hz, 2H), 1.98-2.15 (m, 1H), 2.72 (s, 1H), 2.95 (s, 1H), 3.39 (s, 2H), 4.02 (s, 1H), 4.10 (dd, J = 5.3 Hz, 1H), 4.44 (s, 1H), 4.82 (s, 2H), 6.14 (d, J = 2.3 Hz, 1H), 6.29 (dd, J = 8.0, 2.3 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H). m/z (ES+) [M+H]⁺ = 305.

Step 7: (25)-2-{(35)-l-[(4-azido-2-cyclopropylphenyl)methyl]piperidin-3-yl}propane-l,2-diol (intermediate 5)

Trimethylsilyl azide (0.057 mL, 0.43 mmol) were added dropwise to tert-butyl nitrite (55.9 mg, 0.54 mmol) and tert-butyl [3-cyclopropyl-4-({(35)-3-[(25)-l,2-dihydroxypropan-2- yl]piperidin-l-yl}methyl)phenyl]carbamate (110 mg, 0.36 mmol) in acetonitrile (4 mL) at 0 °C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 3 hours, then concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (gradient elution, 0 to 40%) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (80 mg, 67%). m/z (ES+) [M+H]⁺ = 331.

Intermediate 6, (2.S)-2- {(35)- 1- [(2-chloro-4-ethy nylphenyl)methyl] piperidin-3- yl}propane-l,2-diol

Step 1: 2-chloro-4-{[tri(propan-2-yl)silyl]ethynyl}benzaldehyde

Cuprous iodide (1.74 g, 9.11 mmol) was added to ethynyltriisopropylsilane (9.97 g, 54.68 mmol), Bis(triphenylphosphine)palladium(II) dichloride (3.20 g, 4.56 mmol) and 4-bromo-2- chlorobenzaldehyde (10 g, 45.57 mmol) in triethylamine (100 mL) under nitrogen. The resulting mixture was stirred at rt for 2 hours, then diluted with ethyl acetate (1 L), washed successively with water (3 x 500 mL) and brine (3 x 750 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-3 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (12.80 g, 88 %): 1H NMR (400 MHz, DMSO, 22°C) 5 1.10 (d, J = 4.1 Hz, 21H), 7.59 (dd, J = 8.2, 1.6 Hz, 1H), 7.70 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 10.30 (s, 1H). m/z (ES+) [M+H]⁺ = 321.

Step 2 (2-chloro-4-{ [tri(propan-2-yl)silyl]ethynyl }phenyl)methanol

Sodium borohydride (1.36 g, 35.83 mmol) was added to 2-chloro-4-{ [tri (propan-2 - yl)silyl]ethynyl (benzaldehyde (11.5 g, 35.83 mmol) in AcOH (10 mL) and THF (lOOmL). The resulting mixture was stirred at rt for 2 hours. This mixture was combined with a similar batch starting from 1 g of 2-chloro-4-((triisopropylsilyl)ethynyl)benzaldehyde, then diluted with ethyl acetate (500 mL), washed successively with water (3 x 400 mL) and brine (1 x 400 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using methanol in ethyl acetate (gradient elution, 0-4 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (11.0 g, 88 %): 1H NMR (400 MHz, DMSO) 5 1.08 (d, J = 2.0 Hz, 22H), 4.56 (s, 2H), 5.49 (s, 1H), 7.44 (p, J = 3.1, 2.4 Hz, 2H), 7.55 (d, J = 8.2 Hz, 1H). m/z (ES-) [M-H]' = 305.

Step 3: {[3-chloro-4-(chloromethyl)phenyl]ethynyl(tri(propan-2-yl)silane

Thionyl chloride (4.97 mL, 68.12 mmol) was added to DMF (0.66 mL, 8.52 mmol) and (2- chloro-4-{[tri(propan-2-yl)silyl]ethynyl(phenyl)methanol (5.5 g, 17.03 mmol) in MeCN (50 mL). The resulting mixture was stirred at rt for 1 hour, then quenched with saturated sodium hydrogencarbonate (5 mL), extracted with ethyl acetate (3 x 10 mL), the organic layer was dried over Na2SO4, filtered and evaporated to afford yellow oil. The product was used in the next step directly without further purification. Yellow oil (5.00 g, 86 %): 1H NMR (400 MHz, DMSO) 5 1.09 (d, J = 3.1 Hz, 22H), 4.83 (s, 2H), 7.45 (dd, J = 7.9, 1.7 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H).

Step 4 (25)-2-{(35)-l-[(2-chloro-4-{ [^(propan^-y^silyllethynylJpheny^methylJpiperidin- S-ylJpropane-l^-diol

Potassium carbonate (0.97 g, 7.03 mmol) was added to a solution of {[3-chloro-4- (chloromethyl)phenyl]ethynyl}tri(propan-2-yl)silane (1.2g, 3.52 mmol) and (S)-2-((S)- piperi din-3 -yl)propane-l,2-diol (0.840 g, 5.27 mmol) in DMF (lOmL). The resulting mixture was stirred at rt for 2 hours, then filtered through a pad of Celite and concentrated. Flash Cl 8- chromatography of the residue using acetonitrile in water (gradient elution, 0-70 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (1.30 g, 80 %): 1H NMR (400 MHz, DMSO, 26°C) 5 0.91 (s, 3H), 1.09 (s, 22H), 1.42 (d, J = 12.7 Hz, 1H), 1.65 (q, J = 14.0 Hz, 4H), 1.87 (q, J = 12.3, 11.6 Hz, 2H), 2.73 (s, 2H), 2.89 (s, 1H), 2.95 (d, J = 10.7 Hz, 1H), 3.19 (d, J = 5.5 Hz, 2H), 3.52 (s, 2H), 3.94 (s, 1H), 4.42 (t, J = 5.6 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H). m/z (ES+) [M+H]⁺ = 464.

Step 5: (25)-2-{(35)-l-[(2-chloro-4-ethynylphenyl)methyl]piperidin-3-yl}propane-l,2-diol (intermediate 6).

Potassium fluoride (0.39 g, 6.73 mmol) was added to a solution of (25)-2-{(35)-l-[(2-chloro- 4-{[tri(propan-2-yl)silyl]ethynyl}phenyl)methyl]piperidin-3-yl}propane-l,2-diol (1.25 g, 2.69 mmol) in 10: 1 DMSO-water (11 mL) and was stirred at 80 °C for 2 hours. The reaction mixture was then diluted with ethyl acetate (10 mL), washed successively with water (3 x 10 mL), saturated brine (3 x 10 mL), then dried, filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-50 %) followed by concentration of the appropriate fractions gave the title compound as a colorless oil (0.800 g, 97 %): 1H NMR (400 MHz, DMSO, 26°C) 5 0.91 (s, 4H), 1.43 (d, J = 12.1 Hz, 1H), 1.66 (d, J = 14.0 Hz, 3H), 1.86 (dd, J = 19.2, 10.5 Hz, 2H), 2.54 (s, 1H), 2.72 (d, J = 7.8 Hz, 1H), 2.95 (d, J = 10.4 Hz, 1H), 3.17 (dd, J = 9.8, 3.7 Hz, 3H), 3.52 (s, 2H), 3.95 (s, 1H), 4.29 (s, 1H), 4.43 (s, 1H), 7.4-7.55 (m, 3H). m/z (ES+) [M+H]⁺ = 308. Intermediate 7, 3-azido-2-chlorobenzonitrile

Azidotrimethylsilane (566 mg, 4.92 mmol) was added to 4-amino-3 -chlorobenzonitrile (500 mg, 3.28 mmol) and tert-butyl nitrite (439 mg, 4.26 mmol) in acetonitrile (5 mL) at 0°C. The resulting mixture was stirred at rt for 4 hours, then concentrated. The residue was diluted with ethyl acetate (25 mL), and washed successively with water (1 x 50 mL), brine (2 x 25 mL), then dried (sodium sulfate), filtered and concentrated. Flash silica chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 5 to 10 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (340 mg, 58 %): 1H NMR (400 MHz, DMSO-d6) 5 7.59 (t, J = 8.0 Hz, 1H), 7.73-7.83 (m, 2H).

Intermediate 8, 3-azido-2-fluorobenzonitrile

A solution of sodium nitrite (243 mg, 3.53 mmol) in water (3 mL) was added dropwise during 5 min to a stirred mixture of 3-amino-2-fluorobenzonitrile (400mg, 2.94 mmol), HC1 (1.16 mL, 38.2 mmol) in ethyl acetate (8 mL) at 0°C, over a period of 5 minutes. The resulting mixture was stirred at 0 °C for 1 hour, then sodium azide (229 mg, 3.53 mmol) in water (3 mL) was added dropwise during 3 min at 0°C and the resulting mixture was stirred at rt for another 3 h. This mixture was combined with a parallel batch starting from 100 mg of 3- amino-2-fluorobenzonitrile, then diluted with ethyl acetate (20 mL), washed successively with water (1 x 10 mL) and brine (1 x 20 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-50 %) followed by concentration of the appropriate fractions gave the title compound as a brown solid (364 mg, 61 %): 1H NMR (300 MHz, DMSO-d6) 5 7.43 (td, J = 7.9, 1.1 Hz, 1H), 7.66-7.81 (m, 2H). Intermediate 9, l-azido-4-methylbenzene

Trimethylsilyl azide (1.29 g, 11.2 mmol) was added to p-toluidine (1 g, 9.33 mmol) and tert- Butylnitrite, tech. (1.44 g, 14.0 mmol) in acetonitrile (10 mL) at 0°C. The resulting mixture was stirred at 0 °C for 15 hours, then concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-10 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (0.800 g, 64 %): 1H NMR (300 MHz, DMSO, 24°C) 5 2.29 (3H, s), 6.99 (1H, d), 7.01 (1H, d), 7.21 (1H, t), 7.23 (1H, t).

Intermediate 10, (25)-2-[(35)-l-{[2-(difluoromethoxy)-4- ethynylphenyl]methyl}piperidin-3-yl]propane-l,2-diol

Step . 2-(difluoromethoxy)-4-{[tri(propan-2-yl)silyl]ethynyl}benzaldehyde

4-bromo-2-(difluoromethoxy)benzaldehyde (1.50 g, 5.98 mmol) was added to Copper(I) iodide (0.228 g, 1.20 mmol), ethynyltriisopropylsilane (1.308 g, 7.17 mmol) and Triphenylphosphine palladium chloride (0.419 g, 0.60 mmol) in triethylamine (11 mL) under nitrogen. The resulting mixture was stirred at rt for 5 hours, then filtered through celite and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-2 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (1.90 g, 90 %): 1H NMR (400 MHz, DMSO, 22°C) 5 0.88-1 (1H, m), 1.09 (26H, d), 7.36-7.51 (3H, m), 7.82 (1H, d), 10.25 (1H, s). m/z (ES+) [M+H]⁺ = 353. Step 2'. (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-{[tri(propan-2- yl)silyl]ethynyl}phenyl]methyl}piperidin-3-yl]propane-l,2-diol

Sodium triacetoxyborohydride (1.804 g, 8.51 mmol) was added to intermediate 1 (0.813 g, 5.11 mmol) and 2-(difluoromethoxy)-4-{ [tri (propan-2 -yl)silyl]ethynyl (benzaldehyde (1.2 g, 3.40 mmol) in di chloroethane (10 mL) over a period of 10 minutes. The resulting mixture was stirred at rt for 15 hours, then diluted with DCM (100 mL), washed successively with water (100 mL) and brine (75 mL), then dried (sodium sulfate), filtered and concentrated. The residue was combined from a parallel batch starting from 300 mg, 0.85 mmol of 2- (difluoromethoxy)-4-{[tri(propan-2-yl)silyl]ethynyl(benzaldehyde. Flash chromatography of the combined residues using methanol in di chloromethane (gradient elution, 0-20 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (1.17 g, 56 %): 1H NMR (300 MHz, DMSO) 5 0.92 (3H, s), 1.10 (21H, d), 1.23 (1H, s), 1.46 (1H, s), 1.65 (3H, d), 2.74 (1H, s), 2.98 (1H, s),3.50 (2H, s), 3.19 (2H, d), 3.99 (1H, s), 4.48 (1H, s), 6.99-7.29 (2H, m), 7.36 (1H, d), 7.51 (1H, s). m/z (ES+) [M+H]⁺ = 496.

(25)-2-[(35)-l-{[2-(difluoromethoxy)-4-ethynylphenyl]methyl}piperidin-3-yl]propane-l,2- diol (Intermediate 10)

Potassium fluoride (211 mg, 3.63 mmol) was added to (25)-2-[(35)-l-{[2-(difluoromethoxy)- 4-{[tri(propan-2-yl)silyl]ethynyl}phenyl]methyl}piperidin-3-yl]propane-l,2-diol (900 mg, 1.82 mmol) in 10: 1 DMSO-water (11 mL). The resulting mixture was stirred at 80 °C for 15 hours. The reaction mixture was then allowed to cool to rt, diluted with ethyl acetate (25 mL), washed successively with water (3 x 10 mL), saturated brine (3 x 10 mL), then dried, filtered and concentrated. The residue was combined with a parallel batch starting from 230 mg, 0.46 mmol of to (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-{[tri(propan-2- yl)silyl]ethynyl}phenyl]methyl}piperidin-3-yl]propane-l,2-diol. Flash C-18 chromatography of the combined residues using acetonitrile in water (gradient elution, 0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (600 mg, 78 %): 1H NMR (300 MHz, DMSO, 23°C) 5 0.91 (3H, s), 1.00 (1H, dt), 1.42 (1H, q), 1.57-1.72 (3H, m), 1.89 (2H, q), 2.75 (1H, d), 2.96 (1H, d), 3.19 (2H, s), 3.51 (2H, s), 4.29 (1H, s), 7.21 (1H, d), 7.26 (1H, d), 7.36 (1H, dd), 7.46 (1H, d). m/z (ES+) [M+H]⁺ = 340.

Intermediate 11, l-azido-4-(2,2-difluoroethoxy)benzene

Z-Butyl nitrite (179 mg, 1.73 mmol) was added to 4-(2,2-difluoroethoxy)aniline (200 mg, 1.15 mmol) and tert-butyl nitrite (179 mg, 1.73 mmol) in acetonitrile (5 mL) at 0°C. The resulting mixture was stirred at rt for 2 hours, then quenched with water (2 mL), extracted with ethyl acetate (2 x 50 mL), dried (sodium sulfate), filtered and concentrated to afford the title compound as a yellow oil (200mg). This material was used as such without further purification in the next step.

Intermediate 12, l-azido-4-(cyclopropyloxy)benzene

Trimethylsilyl azide (309 mg, 2.68 mmol) was added to /-Butylnitrite (415 mg, 4.02 mmol) and 4-cyclopropoxyaniline (200 mg, 1.34 mmol) in acetonitrile (3 mL) at 0°C. The resulting mixture was stirred at 0 °C for 14 hours, then quenched with water (2 mL), extracted with ethyl acetate (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (gradient elution, 0-80 %) followed by concentration of the appropriate fraction gave the title compound as a black liquid (140 mg, 60 %): 1H NMR (400 MHz, DMSO) 5 0.61-0.67 (m, 2H), 0.77 (dt, J = 7.4, 5.5 Hz, 2H), 3.83 (tt, J = 6.0, 2.9 Hz, 1H), 7.04-7.11 (m, 4H).

Intermediate 13, (25)-2-[(35)-l-{[2-(difluoromethoxy)-4- ethynylphenyl] (²Hi)methyl} piperidin-3-yl] propane-1 ,2-diol

Step . [4-bromo-2-(difhioromethoxy)phenyl](²H2)methanol

Lithium aluminium deuteride (0.896 g, 21.35 mmol) was added to methyl 4-bromo-2- (difluoromethoxy)benzoate (3 g, 10.67 mmol, CAS RN 553672-24-5) in THF (30 mL) at - 20°C under nitrogen. The resulting mixture was stirred at -20 °C for 1 hour, then quenched with aq. saturated ammonium chloride (75 mL) and extracted with ethyl acetate (3 x 125 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-20 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (2.10 g, 77 %): 1H NMR (400 MHz, DMSO, 27°C) 5 5.28 (s, 1H), 6.98-7.55 (m, 4H).

Step 2'. 4-bromo-l-[chloro(²H2)methyl]-2-(difluoromethoxy)benzene

A,A-Dimethylformamide (0.152 mL, 1.96 mmol) was added to thionyl chloride (1.145 mL, 15.68 mmol) and [4-bromo-2-(difluoromethoxy)phenyl](²H2)methanol (1 g, 3.92 mmol) in acetonitrile (10 mL) at 0°C. The resulting mixture was stirred at rt for 2 hours, then quenched with aq. saturated sodium hydrogen carbonate (100 mL), extracted with EtOAc (3 x 75 mL). The organic layers were combined, then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-50 %) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (1.00 g, 93 %): 1H NMR (400 MHz, DMSO, 26°C) 5 7.2-7.59 (m, 4H).

Step 3: (25)-2-[(35)-l-{[4-bromo-2-(difluoromethoxy)phenyl](²H2)methyl}piperidin-3- yl]propane-l,2-diol

Potassium carbonate (606 mg, 4.39 mmol) was added to intermediate 1 (419 mg, 2.63 mmol) and 4-bromo-l -[chi oro(²H2)methyl]-2-(difluorom ethoxy )benzene (600 mg, 2.19 mmol) in DMF (6 mL). The resulting mixture was stirred at rt for 2 hours, then filtered through a pad of celite. The filtrate was purified by flash C18 chromatography using acetonitrile in water (gradient elution, 0-60%, water was buffered with 0.05% trifluoroacetic acid) followed by concentration of the appropriate fractions which gave the title compound as a pale yellow solid (640 mg, 73 %): m/z (ES+) [M+H]⁺ = 396.

Step 4 (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl] (²H2)methyl }piperidin-3-yl]propane- 1 ,2-diol

Triphenylphosphine palladium chloride (106 mg, 0.15 mmol) was added to copper(I) iodide (57.7 mg, 0.30 mmol), (25)-2-[(35)-l-{[4-bromo-2-(difluoromethoxy)phenyl](²H2)methyl} piperi din-3 -yl]propane-l,2-diol (600 mg, 1.51 mmol) and ethynyltriisopropyl silane (331 mg, 1.82 mmol) in triethylamine (7 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours, then allowed to reach rt, diluted with DCM (100 mL), washed successively with water (100 mL) and brine (75 mL), then dried (sodium sulfate), filtered and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (gradient elution, 0- 70%) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (520 mg, 69 %): m/z (ES+) [M+H]⁺ = 498.

Step 5: (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-ethynylphenyl](²H2)methyl}piperidin-3- yl]propane-l,2-diol (Intermediate 13)

Potassium fluoride (140 mg, 2.41 mmol) was added to (25)-2-[(35)-l-{[2-(difluoromethoxy)- 4-{[tri(propan-2-yl)silyl]ethynyl}phenyl](²H2)methyl}piperidin-3-yl]propane-l,2-diol (480 mg, 0.96 mmol) in DMSO (5 mL) and water (0.5 mL). The resulting mixture was stirred at 80 °C for 2 hours, then allowed to cool to rt, diluted with ethyl acetate (25 mL), washed successively with water (3 x 10 mL), brine (3 x 10 mL), then dried, filtered and concentrated. Flash C18-flash chromatography of the residue using acetonitrile in water (gradient elution, 0- 60%) followed by concentration of the appropriate fractions gave the title compound as a yellow oil (320 mg, 97 %): 1H NMR (400 MHz, DMSO-d6, 23°C) 5 0.91 (s, 3H), 0.96-1.04 (m, 1H), 1.41 (d, J = 13.0 Hz, 1H), 1.65 (q, J = 12.6 Hz, 3H), 1.81-1.93 (m, 2H), 2.73 (d, J = 11.5 Hz, 1H), 2.95 (d, J = 10.7 Hz, 1H), 3.19 (d, J = 1.4 Hz, 2H), 4.30 (s, 1H), 7.03-7.41 (m, 3H), 7.47 (d, J = 7.9 Hz, 1H).

Intermediate 14: (25)-2-{(35)-l-[(4-ethynyl-2-methoxyphenyl)methyl]piperidin-3- yl}propane-l,2-diol

Step . 2-methoxy-4-{[tri(propan-2-yl)silyl]ethynyl}benzaldehyde Triphenylphosphine palladium chloride (228 mg, 0.33 mmol) was added to ethynyltriisopropyl silane (712 mg, 3.91 mmol), 4-bromo-2-methoxybenzaldehyde (700 mg, 3.26 mmol, CAS RN 43192-33-2) and copper(I) iodide (62.0 mg, 0.33 mmol) in triethylamine (7 mL) at rt under nitrogen. The resulting mixture was stirred at rt for 16 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), washed successively with water (1 x 20 mL), brine (1 x 20 mL), dried (sodium sulfate) filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-20 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (630 mg, 61 %): 1H NMR (300 MHz, DMSO-d6) 5 1.05-1.12 (21H, m), 3.93 (2H, s), 7.12 (1H, d), 7.17-7.24 (1H, m), 7.66 (1H, d), 10.30 (1H, s).

Step 2: (25)-2-{(35)-l-[(2-methoxy-4-{[tri(propan-2- yl)silyl]ethynyl(phenyl)methyl]piperidin-3-yl(propane-l,2-diol

Intermediate 1 (315 mg, 1.98 mmol) was added to 2-methoxy-4-{[tri(propan-2- yl)silyl]ethynyl (benzaldehyde (570 mg, 1.80 mmol) in acetic acid (0.103 mL, 1.80 mmol) and methanol (4 mL) over a period of 10 minutes followed by addition of sodium cyanoborohydride (226 mg, 3.60 mmol). The resulting mixture was stirred at 25 °C for 18 hours.

Step 3 : (2S)-2-{ (35)- 1 -[(4-ethynyl-2-methoxyphenyl)methyl]piperi din-3 -yl (propane- 1 ,2-diol (intermediate 14)

(25)-2-{(35)-l-[(2 -methoxy -4-{[tri (propan-2-yl)silyl]ethynyl(phenyl)methyl]piperidin-3- yl(propane-l,2-diol (540 mg, 1.17 mmol) was added to potassium fluoride (341 mg, 5.87 mmol) in DMSO (3.6 mL) and water (0.4 mL). The resulting mixture was stirred at 40 °C for 16 hours. The reaction mixture was allowed to cool to rt, then purified by C18-flash chromatography, elution gradient 0 to 70% acetonitrile in water. Appropriate fractions were concentrated to afford the title compound as a white solid (300 mg, 84 %): 1H NMR (300 MHz, DMSO-d6, 23°C) 5 0.95 (3H, s), 1.08-1.26 (1H, m), 1.62 (2H, dt), 1.81 (1H, d), 1.95 (1H, t), 2.79 (2H, q), 3.20 (3H, s), 3.46 (1H, d), 3.85 (3H, s), 4.25 (2H, d), 4.33 (1H, s), 7.07- 7.23 (2H, m), 7.45 (1H, d), 9.36 (1H, s).

Intermediate 15: (25)-2-[(35)-l-{[2-(cyclopropyloxy)-4-ethynylphenyl]methyl}piperidin- 3-yl] propane- 1 ,2-diol

Step . [4-bromo-2-(cyclopropyloxy)phenyl]methanol

2.5 M lithium aluminum hydride solution in THF (1.24 mL, 3.1 mmol) was added to a solution of methyl 4-bromo-2-cyclopropoxybenzoate, prepared similar as described in WO20 18210988 (1.4 g, 5.16 mmol) in THF (15 mL) at 0°C under nitrogen. The resulting solution was stirred at 25 °C for 2 hours. The reaction mixture was then quenched with 2M NaOH (5 mL) and water (3 mL), extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated. Flash column chromatography using ethyl acetate in petroleum ether (0 to 50%, gradient elution) followed by concertation of the appropriate fractions gave the title compound as a white solid (1.0 g, 80 %): 'HNMR (400 MHz, DMSO-t/6) 5 7.49 - 7.27 (m, 2H), 7.15 (dd, J= 8.1, 1.9 Hz, 1H), 5.06 (t, J= 5.6 Hz, 1H), 4.35 (d, J= 5.6 Hz, 2H), 3.90 (tt, J= 6.1, 3.0 Hz, 1H), 1.01 - 0.76 (m, 2H), 0.66 (q, J = 3.5, 3.1 Hz, 2H).

Step 2 4-bromo-2-(cyclopropyloxy)benzaldehyde

Manganese(IV) oxide (215 mg, 2.47 mmol) was added to (4-bromo-2- cyclopropoxyphenyl)methanol (200 mg, 0.82 mmol) in acetonitrile (8 mL) at 25°C under nitrogen. The resulting solution was stirred at 80°C for 3 hours, then filtered through silica to afford the title compound which was used without further purification in the next step (0.170 g, 86 %): 'HNMR (400 MHz, DMSO-t/6) 5 10.20 (d, J= 0.8 Hz, 1H), 7.70 (d, J= 1.8 Hz, 1H), 7.61 (d, J= 8.3 Hz, 1H), 7.32 (ddd, J= 8.2, 1.8, 0.8 Hz, 1H), 4.13 (tt, J= 6.1, 3.0 Hz, 1H), 0.94 - 0.75 (m, 4H).

Step 3 2-(cyclopropyloxy)-4-{ [tri (propan-2 -yl)silyl]ethynyl (benzaldehyde

Triphenylphosphine palladium chloride (87 mg, 0.12 mmol) were added to ethynyltriisopropyl silane (272 mg, 1.49 mmol), 4-bromo-2-(cyclopropyloxy)benzaldehyde (300 mg, 1.24 mmol) and copper(I) iodide (23.70 mg, 0.12 mmol) in triethylamine (3 mL) at rt under nitrogen. The resulting mixture was stirred at RT for 16 hours, then diluted with EtOAc (20 mL), and washed successively with water (1 x 20 mL), brine (1 x 20 mL), dried (sodium sulfate), filtered and concentrated. Flash column chromatography using ethyl acetate in petroleum ether (0 to 20%, gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (330 mg, 77 %): 1H NMR (300 MHz, DMSO, 23°C) 5 0.71-0.92 (4H, m), 1.10 (21H, d), 4.14 (1H, tt), 7.16 (1H, dt), 7.46 (1H, d), 7.66 (1H, d), 10.21 (1H, d).

Step 4 (25)-2-[(35)-l-{[2-(cyclopropyloxy)-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl] methyl}piperidin-3-yl]propane-l,2-diol

Ill

Intermediate 1 (159 mg, 1.00 mmol) was added to 2-cyclopropoxy-4- ((triisopropylsilyl)ethynyl)benzaldehyde (310 mg, 0.90 mmol) and acetic acid (0.052 mL, 0.90 mmol) in MeOH (4 mL) over a period of 10 minutes . then added Sodium cyanoborohydride (114 mg, 1.81 mmol). The resulting mixture was stirred at 25 °C for 18 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 90% acetonitrile in water. Appropriate fractions were concentrated to dryness to afford the title compound as a colourless oil (380 mg, 86 %): 1H NMR (400 MHz, DMSO) 5 0.71-0.88 (4H, m), 0.94 (3H, s), 1.11 (22H, d), 1.5-1.72 (2H, m), 1.79-2 (2H, m), 2.74 (2H, dt), 3.17 (3H, s), 3.29 (1H, d), 3.37 (1H, d), 4.04 (1H, dt), 7.18 (1H, dd), 7.37 (1H, d), 7.47 (1H, d).

Step 5: (25)-2-[(35)-l-{[2-(cyclopropyloxy)-4-ethynylphenyl]methyl}piperidin-3-yl]propane- 1,2-diol (intermediate 15)

(25)-2-[(35)-l-{[2-(cyclopropyloxy)-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl] methyl}piperidin-3-yl]propane-l,2-diol (360 mg, 0.74 mmol) was added to potassium fluoride (215 mg, 3.71 mmol) in DMSO (3.6 mL) and water (0.4 mL). The resulting mixture was stirred at 40 °C for 16 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 70% MeCN in water. Pure fractions were concentrated to afford the title compound as a white solid (230 mg, 94 %): 1H NMR (400 MHz, DMSO, 26°C) 5 0.64-0.76 (2H, m), 0.81 (2H, ddd), 0.91 (3H, s), 0.93-1.1 (1H, m), 1.47 (1H, t), 1.64 (2H, s), 1.71 (1H, ddt), 1.97-2.13 (2H, m), 2.83 (1H, d), 3.00 (1H, d), 3.57 (2H, d), 3.92 (1H, tt), 4.19 (1H, s), 7.08 (1H, dd), 7.3-7.36 (2H, m), 8.21 (1H, s).

Intermediate 16: (25)-2-{(35)-l-[(2-cyclopropyl-4-ethynylphenyl)methyl]piperidin-3- yl}propane-l,2-diol

Step . methyl 4-bromo-2-cyclopropylbenzoate l,l'-Bis(diphenylphosphino)ferrocenedi chloropalladium (II) di chloromethane adduct (2.395 g, 2.93 mmol) was added to potassium phosphate, tribasic (18.68 g, 87.99 mmol), methyl 4- bromo-2-iodobenzoate (10 g, 29.33 mmol) and cyclopropylboronic acid (3.02 g, 35.20 mmol) in toluene (20 mL) and water (5 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 12 hours. The reaction mixture was filtered through celite and applied to silica. Flash chromatography, elution gradient 0 to 10% ethyl acetate in petroleum ether, followed by concentration of the appropriate fractions gave the title compound as a yellow solid (7.20 g, 96 %): 1H NMR (300 MHz, DMSO, 24°C) 5 0.64-0.72 (m, 2H), 0.89-0.96 (m, 2H), 2.44-

2.49 (m, 1H), 3.79 (s, 3H), 7.13 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.3, 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H).

Step 2 methyl 2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}benzoate

Triphenylphosphine palladium chloride (1.651 g, 2.35 mmol) was added to ethynyltriisopropyl silane (5.15 g, 28.22 mmol), methyl 4-bromo-2-cyclopropylbenzoate (6 g, 23.52 mmol) and copper(I) iodide (0.448 g, 2.35 mmol) in triethylamine (10 mL) at rt under nitrogen, then stirred for 16 h. This reaction mixture was combined from a parallel batch starting from methyl 4-bromo-2-cyclopropylbenzoate (1 g, 3.92 mmol), then concentrated. The residue was diluted with ethyl acetate (50 mL), washed successively with water (1 x50 mL) and brine (1 x 75 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-30 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (8.40 g, 86 %): 1H NMR (400 MHz, DMSO) 5 0.67-0.72 (2H, m), 0.93-0.99 (3H, m), 1.08 (23H, d), 3.85 (3H, s), 7.03 (1H, d), 7.33 (1H, dd), 7.69 (1H, d).

Step 3: (2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl)methanol

Methyl 2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}benzoate (7.35 g, 20.61 mmol) was added to lithium aluminium hydride (4.95 mL, 12.37 mmol) in THF (100 mL) at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 2 hours. The reaction mixture was then poured onto ice (75 mL), extracted into ethyl acetate (1 x 100 mL), dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-50 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (6.00 g, 89 %): 1H NMR (300 MHz, DMSO, 22°C) 5 0.55-0.63 (2H, m), 0.83-0.91 (2H, m), 1.07 (21H, s), 1.88 (1H, tt), 4.68 (2H, s), 5.27 (1H, d), 6.96 (1H, d), 7.26 (1H, dd), 7.39 (1H, d).

Step 4 { [4-(chloromethyl)-3-cyclopropylphenyl]ethynyl}tri(propan-2-yl)silane

(2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl)methanol (5.75g, 17.50 mmol) were added to thionylchloride (2.55 mL, 35.00 mmol) and 7V,7V-dimethylformamide (0.128 g, 1.75 mmol) in acetonitrile (60 mL) at rt under nitrogen, then stirred for 4 h. The reaction mixture was then quenched with ice (100 mL), extracted with ethyl acetate (1 x 100 mL) and the organic layer was washed successively with water (1 xl50 mL), brine (1 x 150 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-40 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (5.70 g, 94 %): 1H NMR (300 MHz, DMSO, 23°C) 5 0.69 (2H, dd), 0.92-1.01 (2H, m), 1.07 (22H, s), 2.07 (1H, tt), 4.92 (2H, s), 7.01 (1H, d), 7.26 (1H, dd), 7.39 (1H, d).

Step 5: (25)-2-{(35)-l-[(2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl)methyl] piperi din-3 -yl (propane- 1 ,2-diol

{[4-(chloromethyl)-3-cyclopropylphenyl]ethynyl}tri(propan-2-yl)silane (1.8 g, 5.19 mmol) was added to intermediate 1 (0.909 g, 5.71 mmol) and potassium carbonate (1.434 g, 10.37 mmol) in 7V,7V-dimethylformamide (20 mL) at rt under nitrogen. The resulting mixture was stirred at rt for 15 hours, then quenched with water (50 mL), extracted with ethyl acetate (l x 50 mL) and the organic layer was washed successively with water (1 x 50 mL), brine (1 x 50 mL), then dried (sodium sulfate), filtered and concentrated. C18-flash chromatography of the residue using acetonitrile in water (gradient elution, 0-70 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (2.00 g, 82 %): 1H NMR (400 MHz, DMSO-d6, 24°C) 5 0.60 (2H, td), 0.91 (4H, s), 1.08 (23H, s), 1.39 (1H, d), 1.64 (3H, dt), 1.83 (2H, t), 2.10 (1H, tt), 2.71 (1H, d), 2.97 (1H, d), 3.19 (2H, s), 3.49-3.61 (2H, m), 3.94 (1H, s), 4.42 (1H, s), 6.97 (1H, d), 7.22 (1H, dd), 7.28 (1H, d).

Step 6: (25)-2-{(35)-l-[(2-cyclopropyl-4-ethynylphenyl)methyl]piperidin-3-yl}propane-l,2- diol (intermediate 16)

(25)-2-{(35)-l-[(2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl)methyl] piperidin-3- yl}propane-l,2-diol (L95g, 4.15 mmol) was added to potassium fluoride (0.482 g, 8.30 mmol) in DMSO (20 mL) and water (2 mL) at rt under nitrogen. The resulting mixture was stirred at 40 °C for 15 hours, then diluted with water (75 mL) and extracted with ethyl acetate (75 mL). The organic layer was washed successively with water (1 x 75 mL) and brine (1 x 75 mL), then dried (sodium sulfate), filtered and concentrated. C18-flash chromatography of the residue using acetonitrile in water (gradient elution, 0-70 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (1.300 g, 100 %): 1H NMR (300 MHz, DMSO-d6, 22°C) 5 0.69 (2H, s), 0.94 (5H, s), 1.12 (1H, d), 1.67 (2H, s), 1.82 (2H, s), 2.15 (1H, s), 3.20 (2H, d), 3.29 (1H, s), 3.48 (1H, s), 4.19-4.59 (3H, m), 4.70 (1H, d), 7.06 (1H, s), 7.37 (2H, t), 9.33 (1H, s).

Intermediate 17: l-azido-3-methoxycyclobutane

Step 1: 3 -methoxy cyclobutyl methanesulfonate

Triethylamine (0.41 mL, 2.94 mmol) was added to 3 -methoxy cyclobutan-l-ol (300 mg, 2.94 mmol, CAS RN 1432680-25-5) and methanesulfonyl chloride (336 mg, 2.94 mmol) in dichloromethane (10 mL) at 0°C under nitrogen. The resulting mixture was stirred at rt for 3 hours, then diluted with ethyl acetate (50 mL), and washed successively with water (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product as a yellow solid (400 mg) used without further purification in the next step.

Step 2'. l-azido-3 -methoxy cyclobutane (intermediate 17)

Sodium azide (162 mg, 2.50 mmol) was added to 3 -methoxy cyclobutyl methanesulfonate (300 mg, 1.66 mmol) and sodium azide (162 mg, 2.50 mmol) in DMF (1 mL) at rt. The resulting mixture was stirred at 70 °C for 6 hours, then diluted with ethyl acetate (20 mL), and washed successively with water (2 x 20 mL) and brine (2 x 20 mL), then dried (sodium sulfate), filtered and concentrated to afford crude product (15 mg) which was used as such in the next step.

Intermediate 18: (25)-2-{(35)-l-[(2-cyclopropyl-4-ethynylphenyl)(²H2)methyl]piperidin- 3-yl}propane-l,2-diol

Step 1: (4-bromo-2-cyclopropylphenyl)(²H2)methanol

Lithium borodeuturide (0.987 g, 23.52 mmol) was added to methyl 4-bromo-2- cyclopropylbenzoate (3 g, 11.76 mmol, from step 1, intermediate 16) in THF (3 mL) at -20°C under nitrogen. The resulting mixture was stirred at -20 °C for 1 hour. The reaction mixture was then quenched with saturated ammonium chloride (75 mL) and extracted with ethyl acetate (3 x 150 mL), the organic layer was dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-30 %) followed by concentration of the appropriate fraction gave the title compound as a yellow oil (2.60 g, 97 %): 1H NMR (400 MHz, DMSO, 24°C) 5 0.56-0.66 (m, 2H), 0.84- 0.93 (m, 2H), 1.91-1.97 (m, 1H), 7.07 (d, J = 1.8 Hz, 1H), 7.31-7.37 (m, 2H).

Step 2'. 4-bromo-2-cyclopropyl(/< /777)7-²H)benzaldehyde

Manganese(IV) oxide (30.7 g, 353.54 mmol) was added to (4-bromo-2- cyclopropylphenyl)(²H2)methanol (2.7 g, 11.78 mmol) in dichloromethane (100 mL). The resulting mixture was stirred at 40 °C for 2 hours. The mixture was filtered through a pad of celite and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-30 %) followed by concentration of the appropriate fraction gave the title compound as a yellow oil (2.6 g, 98%): 1H NMR (400 MHz, DMSO) 5 0.82-0.88 (m, 2H), 0.99-1.09 (m, 3H), 2.77 (tt, J = 8.4, 5.3 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H).

Step 3: 2-cyclopropyl-4-{ [tri(propan-2-yl)silyl]ethynyl J(/r>/77q7-²H)benzaldehyde

Triphenylphosphine palladium chloride (0.466 g, 0.66 mmol) was added to copper(I) iodide (0.253 g, 1.33 mmol), ethynyltriisopropylsilane (1.452 g, 7.96 mmol) and 4-bromo-2- cyclopropylbenzaldehyde-dl (1.5 g, 6.63 mmol) in triethylamine (15 mL) under nitrogen. The resulting mixture was stirred at rt for 2 hours, then concentrated. The residue was diluted with ethyl acetate (150 mL), washed successively with water (3 x 100 mL) and brine (3 x 100 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-3 %) followed by concentration of the appropriate fraction gave the title compound as a yellow oil (1.60 g, 74 %): 1H NMR (400 MHz, DMSO-d6, 27°C) 5 0.77-0.85 (m, 2H), 1.03-1.06 (m, 2H), 1.10 (d, J = 3.4 Hz, 21H), 2.72 (tt, J = 8.6, 5.4 Hz, 1H), 7.16 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H).

Step 4'. (25)-2-{(35)-l-[(2-cyclopropyl-4-{[tri(propan-2-yl)silyl]ethynyl}phenyl)(²H2)methyl] piperi din-3 -yl (propane- 1 ,2-diol

Sodium cyanoborodeuteride (0.402 g, 6.11 mmol) was added to intermediate 1 (0.729 g, 4.58 mmol) and 2-cyclopropyl-4-{ [tri(propan-2-yl)silyl]ethynyl }(/b/w /-²H)benzaldehyde (1.0 g, 3.05 mmol) in Methanol-d4 (10 mL) . The resulting mixture was stirred at rt for 2 hours. The crude product was purified by flash C18-flash chromatography, elution gradient 0 to 70% MeCN in water. Pure fractions were concentrated to dryness to afford the title compound as a yellow solid (0.47 g, 33 %): 1H NMR (400 MHz, DMSO, 27°C) 5 0.70 (dq, J = 12.1, 7.4, 6.0 Hz, 2H), 0.95-1.01 (m, 5H), 1.10 (d, J = 2.2 Hz, 21H), 1.18 (t, J = 7.2 Hz, 1H), 1.62 (d, J = 13.4 Hz, 1H), 1.71 (d, J = 13.3 Hz, 1H), 1.79 (d, J = 14.1 Hz, 1H), 1.92 (d, J = 14.3 Hz, 1H), 2.17 (ddd, J = 13.7, 8.5, 5.3 Hz, 1H), 2.65 (s, 2H), 3.22 (s, 2H), 4.27 (s, 1H), 4.66 (s, 1H), 7.04 (d, J = 1.7 Hz, 1H), 7.34 (dd, J = 7.9, 1.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H).

Step 5: (25)-2-{(35)-l-[(2-cyclopropyl-4-ethynylphenyl)(²H2)methyl]piperidin-3-yl}propane- 1,2-diol (Intermediate 18)

Potassium fluoride (139 mg, 2.38 mmol) was added to (25)-2-{(35)-l-[(2-cyclopropyl-4- {[tri(propan-2-yl)silyl]ethynyl}phenyl)(²H2)methyl] piperidin-3-yl}propane-l,2-diol (450 mg, 0.95 mmol) in DMSO (5 mL) and water (0.5 mL). The resulting mixture was stirred at 80 °C for 2 hours. The crude product was then purified by flash C18-flash chromatography, elution gradient 0 to 60% MeCN in water. Pure fractions were evaporated to dryness to afford the title compound as a yellow oil (270 mg, 90 %): 1H NMR (400 MHz, DMSO, 23°C) 5 0.63 (h, J = 3.4 Hz, 2H), 0.9-0.95 (m, 6H), 0.97-1.07 (m, 1H), 1.44 (dd, J = 14.3, 10.6 Hz, 1H), 1.62- 1.74 (m, 4H), 1.97-2.08 (m, 2H), 2.12 (td, J = 8.5, 4.3 Hz, 1H), 2.81 (d, J = 11.1 Hz, 1H), 3.02 (s, 2H), 3.19 (s, 2H), 4.08 (s, 1H), 7.02 (s, 1H), 7.23-7.27 (m, 1H), 7.31 (d, J = 7.8 Hz, 1H).

Intermediate 19: 2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzaldehyde

To a degassed mixture of 4-bromo-2-(difluoromethoxy)benzaldehyde (2 g, 7.97 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.327 g, 9.16 mmol) and potassium acetate (1.564 g, 15.93 mmol) in 1,4-dioxane (20 mL) was added [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.488 g, 0.60 mmol), then degassed once more using nitrogen. The mixture was then stirred 100 °C for 1 h, allowed to cool and partitioned between ethyl acetate (50 mL) and water (40 mL). The organic layer was washed with brine (1 x 40 mL), dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue (dissolved in dichloromethane) using ethyl acetate in heptane (gradient elution 12.5 - 17 %) followed by concentration of the appropriate fractions gave the title compound as colorless oil that solidified upon standing (2.2 g, 93%): 1H NMR (500 MHz, DMSO-d6) 1.32 (12H, s), 7.26 - 7.62 (2H, m), 7.68 (1H, dt), 7.86 (1H, d), 10.31 (1H, d).

Intermediate 20: 4-(4-bromo-l//-pyrazol-l-yl)-3-methylbenzonitrile

4-fluoro-3 -methylbenzonitrile (1 g, 7.40 mmol), 4-bromo-lH-pyrazole (1.196 g, 8.14 mmol) and cesium carbonate (3.62 g, 11.10 mmol) in A i methyl form am ide (5 mL) was stirred at 70°C over the weekend. The reaction mixture was then partitioned between ethyl acetate (20 mL) and water (20 mL), and the water layer was extracted with ethyl acetate (1 x 20 mL). The combined organic layers were washed successively with water (3 x 10 mL) and brine (1 x 10 mL), then dried (sodium sulfate), filtered and concentrated which gave the crude title compound as a colourless oil which solidified upon standing (1.9 g).

Intermediate 21: 4-{4-[3-(difluoromethoxy)-4-formylphenyl]-lH-pyrazol-l-yl}-3- methylbenzonitrile

A mixture of intermediate 19 (0.25 g, 0.84 mmol), intermediate 20 (0.220 g, 0.84 mmol), (2- Dicy clohexylphosphino-2 ',4 ', 6 ' -tri i sopropyl- 1 , 1 '-biphenyl) [2-(2 '-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate (0.035 g, 0.04 mmol) and sodium carbonate (0.267 g, 2.52 mmol) in THF (4 mL) and water (1.5 mL) was degassed with nitrogen, then heated to 75 °C under stirring for 2 h. The mixture was allowed to cool to rt, partitioned between ethyl acetate (20 mL) and water (5 mL), then the organic layer was washed with brine (1 x 10 mL), dried (sodium sulfate), filtered and concentrated which gave a yellow solid. The solid was triturated with ethyl acetate (5 mL), filtered, washed with ethyl acetate and air dried to provide the title compound as a yellow solid (0.17 g, 57 %): 1H NMR (500 MHz, DMSO) 2.40 (3H, s), 7.43 (1H, t), 7.67 - 7.75 (2H, m), 7.80 (1H, dt), 7.88 (2H, dd), 7.94 - 8.01 (1H, m), 8.47 (1H, d), 8.92 (1H, d), 10.23 (1H, s).

Intermediate 22: 2-(difluoromethoxy)-4-[ l-(oxan-4-yl)-lZ/-pyrazol-4-yl]benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.20 g, 0.67 mmol) and 4-bromo-l-(oxan-4-yl)-l/7-pyrazole (0.155 g, 0.67 mmol, CAS RN 1040377-02-3). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20- 50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.13 g, 60 %): 1H NMR (500 MHz, DMSO) 1.9 - 2.09 (4H, m), 3.50 (2H, td), 3.95 - 4.03 (2H, m), 4.46 (1H, tt), 7.44 (1H, t), 7.59 - 7.63 (1H, m), 7.66 - 7.71 (1H, m), 7.84 (1H, d), 8.12 (1H, d), 8.56 (1H, d), 10.22 (1H, d).

Intermediate 23: 4-( 1 -benzyl- LH-pyrazol-4-yl)-2-(difluoromethoxy)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.20 g, 0.67 mmol) and l-benzyl-4-bromo-lZ7-pyrazole (0.159 g, 0.67 mmol, CAS RN 50877-41-3). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20- 50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.18 g, 82 %): 1H NMR (500 MHz, DMSO) 5.38 (2H, s), 7.26 - 7.44 (6H, m), 7.58 (1H, d), 7.63 - 7.68 (1H, m), 7.82 (1H, d), 8.12 (1H, d), 8.54 (1H, d), 10.20 (1H, s).

Intermediate 24: 2-(difluoromethoxy)-4-[l-(2-phenylethyl)-lH-pyrazol-4- yl] benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.20 g, 0.67 mmol) and 4-bromo-l-(2-phenylethyl)-l/7-pyrazole (0.168 g, 0.67 mmol, CAS RN 261948-25-8). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.18 g, 78 %): 1H NMR (500 MHz, DMSO) 3.15 (2H, t), 4.39 (2H, t), 7.20 (3H, td), 7.24 - 7.31 (2H, m), 7.39 - 7.66 (3H, m), 7.81 (1H, d), 8.09 (1H, d), 8.34 (1H, d), 10.20 (1H, d).

Intermediate 25: 2-(difl uoromethoxy)-4-(l -phenyl- l//-pyrazol-4-yl (benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.21 g, 0.70 mmol) and 4-bromo-l-(2-phenylethyl)-l/7-pyrazole (0.157 g, 0.70 mmol, CAS RN 15115-52-3). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.22 g, 99 %): 1H NMR (500 MHz, DMSO) 7.28 - 7.61 (4H, m), 7.74 (1H, d), 7.81 (1H, ddd), 7.87 - 7.94 (3H, m), 8.42 (1H, d), 9.27 (1H, d), 10.24 (1H, d).

Intermediate 26: 2-(difluoromethoxy)-4-[l-(4-fluorophenyl)-lH-pyrazol-4- yl] benzaldehyde Prepared similar as described for intermediate 21 from intermediate 19 (0.21 g, 0.70 mmol) and 4-bromo-l-(4-fluorophenyl)-U/-pyrazole (0.170 g, 0.70 mmol, CAS RN 957062-56-5). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.13 g, 58 %): 1H NMR (500 MHz, DMSO) 7.27 - 7.59 (4H, m), 7.72 (1H, d), 7.77 - 7.82 (1H, m), 7.89 (1H, d), 7.91 - 7.96 (2H, m), 8.41 (1H, d), 9.23 (1H, d), 10.23 (1H, d).

Intermediate 27: 2-(difluoromethoxy)-4-{l-[(oxan-4-yl)methyl]-lZ/-pyrazol-4- yl} benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.21 g, 0.70 mmol) and 4-bromo-l-[(oxan-4-yl)methyl]-U/-pyrazole (0.171 g, 0.70 mmol, CAS RN 1040377-11- 4). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.11 g, 47 %): 1H NMR (500 MHz, DMSO) 1.18 - 1.33 (2H, m), 1.38 - 1.45 (2H, m), 2.09 (1H, ddp), 3.25 (2H, dd), 3.83 (2H, ddd), 4.05 (2H, d), 7.21 - 7.61 (2H, m), 7.64 (1H, dt), 7.82 (1H, d), 8.09 (1H, d), 8.43 (1H, d), 10.20 (1H, s).

Intermediate 28: 4-bromo-l-[4-(difluoromethoxy)phenyl]-lH-pyrazole

A mixture of (4-(difluoromethoxy)phenyl)boronic acid (1.023 g, 5.44 mmol), 4-bromo-lH- pyrazole (0.5g, 3.40 mmol), diacetoxycopper (0.989 g, 5.44 mmol) in dichloromethane (40 mL) and pyridine (0.824 mL, 10.21 mmol) was warmed to 30°C with stirring overnight. The reaction mixture was worked up by filtering through a pad of celite and washing the solids with ethyl acetate. The organic layer was concentrated and the residue purified by column chromatography using ethyl acetate in heptane (5 - 12 %, stepwise gradient elution). Concentration of the appropriate fractions gave a colorless oil which solidified upon standing (0.28 g, 28 %): 1H NMR (500 MHz, DMSO) 7.04 - 7.09 (1H, m), 7.11 - 7.44 (3H, m), 7.83 - 7.9 (2H, m), 8.78 (1H, d).

Intermediate 29: 2-(difluoromethoxy)-4-{l-[4-(difluoromethoxy)phenyl]-lH-pyrazol-4- yl} benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.25 g, 0.84 mmol) and intermediate 28 (0.255 g, 0.88 mmol). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 16-25 %) followed by concentration of the appropriate fractions gave the title compound as a slightly yellow solid (0.15 g, 47 %): 1H NMR (500 MHz, DMSO) 7.13 - 7.61 (4H, m), 7.73 (1H, s), 7.80 (1H, dt), 7.89 (1H, d), 7.92 - 7.99 (2H, m), 8.42 (1H, s), 9.25 (1H, d), 10.23 (1H, s).

Intermediate 30 : 4-iodo- 1- [(lr, 3r)-3-methoxy cyclobutyl] - 1 //-py r azole

Step r. l-[(lr,3r)-3-(benzyloxy)cyclobutyl]-4-iodo-U/-pyrazole

A mixture of (l ,3 )-3-(benzyloxy)cyclobutyl 4-m ethylbenzene- 1 -sulfonate (1.885 g, 5.67 mmol, prepared as described m ACS Med. Chem. Lett. 2015, 6, 6, 655-659), 4-iodo-UT- pyrazole (1.1 g, 5.67 mmol), and cesium carbonate (5.54 g, 17.01 mmol) in DMF (12 mL), was heated with stirring at 80°C for 3 hours. The reaction mixture was then allowed to cool to rt, partitioned between ethyl acetate (40 mL) and water (40 mL). The water layer was extracted with ethyl acetate (20 mL), and the combined organic layers were washed with water (3 x 30 mL) and brine (1 x 20 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (5-12 %, stepwise gradient elution) followed by concentration of the appropriate fraction gave the title compound as a colorless oil (1.4 g, 70 %): 1H NMR (500 MHz, CDC13) 2.61 (2H, dddd), 2.7 - 2.8 (2H, m), 4.37 - 4.44 (1H, m), 4.46 (2H, s), 4.92 (1H, ddt), 7.28 - 7.33 (1H, m), 7.35 (4H, d), 7.45 (1H, d), 7.54 (1H, s).

Step 2: (lr,3r)-3-(4-iodo-lH-pyrazol-l-yl)cyclobutan-l-ol

To a stirred solution of l-((lr,3r)-3-(benzyloxy)cyclobutyl)-4-iodo-lH-pyrazole (1.4 g, 3.95 mmol) in dichloromethane (20 mL) under argon at -78 °C was added IM BCh in DCM (11.86 mL, 11.86 mmol) over 10 minutes, then stirred additional 2 h at -78 °C. The reaction mixture was then allowed to reach rt and poured slowly into water (75 mL), then extracted into ethyl acetate (2 x 100 mL), washed with brine (40 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (20-33 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colorless syrup (0.9 g, 86 %): 1H NMR (500 MHz, CDC13) 2.49 - 2.59 (2H, m), 2.83 (2H, dddd), 4.73 (1H, ttd), 4.98 (1H, tt), 7.48 (1H, s), 7.56 (1H, s).

Step 3: 4-iodo-l-[(lr,3r)-3-methoxycyclobutyl]-U/-pyrazole (Intermediate 30)

To a stirred solution of (lr,3r)-3-(4-iodo-lH-pyrazol-l-yl)cyclobutan-l-ol (0.44 g, 1.67 mmol) in dry THF (10 mL) was added sodium hydride (0.133 g, 3.33 mmol) in two portions, then stirred at rt for 20 min followed by the addition of iodomethane (0.207 mL, 3.33 mmol). The reaction mixture was stirred for 1 h, then water (20 mL) was carefully added, followed by extraction into ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (10-20 %, stepwise gradient elution) followed by concentration of the appropriate fractions gave the title compound as a colorless syrup (0.42 g, 91 %): 1H NMR (500 MHz, CDC13) 2.54 (2H, dddd), 2.66 - 2.78 (2H, m), 3.29 (3H, s), 4.19 (1H, ttd), 4.85 - 4.94 (1H, m), 7.45 (1H, d), 7.54 (1H, s).

Intermediate 31: 2-(difluoromethoxy)-4-{l-[( lr,3 )-3-methoxycyclobutyl]-lH-pyrazol-4- yl} benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.25 g, 0.84 mmol) and intermediate 30 (0.245 g, 0.88 mmol). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as a slightly yellow syrup (0.19 g, 70 %): 1H NMR (500 MHz, DMSO) 2.41 - 2.51 (2H, m), 2.6 - 2.69 (2H, m), 3.20 (3H, s), 4.13 - 4.21 (1H, m), 4.96 (1H, tt), 7.42 (1H, t), 7.58 (1H, d), 7.66 (1H, ddd), 7.82 (1H, d), 8.13 (1H, d), 8.54 (1H, d), 10.20 (1H, d).

Intermediate 32: 2-(difl uoromethoxy )-4-(3-methyl-l -phenyl- lH-pyrazol-4- yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.27 g, 0.91 mmol) and 4-bromo-3-methyl-l-phenyl-l/7-pyrazole (0.215 g, 0.91 mmol, CAS RN 50877-45-7). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-25 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.17 g, 57 %): 1H NMR (500 MHz, DMSO) 2.50 (3H, s), 7.28 - 7.61 (5H, m), 7.67 (1H, ddd), 7.85 - 7.89 (2H, m), 7.91 (1H, d), 9.02 (1H, s), 10.26 (1H, s). Intermediate 33: 2-(difl uoromethoxy )-4-(5-methyl-l -phenyl- lH-pyrazol-4- yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.25 g, 0.84 mmol) and 4-bromo-5-m ethyl- 1 -phenyl- 1/7-pyrazole (0.199 g, 0.84 mmol, CAS RN 50877-44-6). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 12-20 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.16 g, 58 %): 1H NMR (500 MHz, DMSO) 2.49 (3H, s), 7.32 - 7.65 (8H, m), 7.92 (1H, d), 8.12 (1H, s), 10.28 (1H, s).

Intermediate 34: 2-(difluoromethoxy)-4-(2-phenyl-l,3-oxazol-5-yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.22 g, 0.74 mmol) and 5-bromo-2-phenyl-l,3-oxazole (0.15 g, 0.67 mmol, CAS RN 92629-11-3). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-17 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.17 g, 81 %): 1H NMR (500 MHz, DMSO) 7.37 - 7.7 (4H, m), 7.85 (1H, d), 7.93 (1H, ddd), 7.98 (1H, d), 8.13 - 8.21 (3H, m), 10.28 (1H, d).

Intermediate 35: 2-(difluoromethoxy)-4-(5-phenyl-l,3-oxazol-2-yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.22 g, 0.74 mmol) and 2-bromo-5-phenyl-l,3-oxazole (0.15 g, 0.67 mmol, CAS RN 129053-70-9). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-17 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.10 g, 47 %): 1H NMR (500 MHz, DMSO) 7.41 - 7.74 (4H, m), 7.91 - 7.96 (2H, m), 8 - 8.06 (3H, m), 8.14 (1H, ddd), 10.33 (1H, d).

Intermediate 36: 2-(difluoromethoxy)-4-(4-phenyl-l,3-oxazol-2-yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.29 g, 0.98 mmol) and 2-bromo-4-phenyl-l,3-oxazole (0.20 g, 0.89 mmol, CAS RN 1060816-19-4). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-17 %) followed by concentration of the appropriate fractions gave the title compound as a yellowish solid (0.22 g, 78 %): 1H NMR (500 MHz, DMSO) 7.39 - 7.74 (4H, m), 7.89 - 7.95 (2H, m), 7.98 (1H, d), 8.04 (1H, d), 8.10 (1H, ddd), 8.91 (1H, s), 10.33 (1H, d).

Intermediate 37: 2-(difluoromethoxy)-4-(2-phenyl-l,3-oxazol-4-yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.24 g, 0.82 mmol) and 2-bromo-4-phenyl-l,3-oxazole (0.20 g, 0.90 mmol, CAS RN 861440-59-7). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-17 %) followed by concentration of the appropriate fractions gave the title compound as a yellowish solid (0.21 g, 82 %): 1H NMR (500 MHz, DMSO) 7.29 - 7.88 (5H, m), 7.91 - 8.01 (2H, m), 8.03 - 8.13 (2H, m), 9.01 (1H, s), 10.28 (1H, s).

Intermediate 38: 2-(difl iioromethoxy)-4-(l -phenyl- l//-pyrazol-3-yl (benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.21 g, 0.72 mmol) and 3 -bromo- 1 -phenyl- I A-pyrazole (0.18 g, 0.81 mmol, CAS RN 50877-46-8). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-20 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.15 g, 52 %): 1H NMR (500 MHz, DMSO) 7.26 (1H, d), 7.35 - 7.68 (4H, m), 7.85 - 8.03 (5H, m), 8.67 (1H, d), 10.28 (1H, d).

Intermediate 39: 4-(3-bromo-l//-pyr:izol-l-yl (benzonit rile

A mixture of 3-bromo- l A-pyrazole (0.5 g, 3.40 mmol), 4-fluorobenzonitrile (0.453 g, 3.74 mmol) and cesium carbonate (1.663 g, 5.10 mmol) in AA-dimethylformamide (3 mL) was stirred at 50 °C for 2 h. The reaction mixture was then partitioned between EtOAc (25 mL) and water (20 mL) and the organic layer was washed with water (2 x 20 mL) and brine (l x 10 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 12-25 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.29 g, 34 %): 1H NMR (500 MHz, DMSO) 6.82 (1H, d), 7.97 - 8.05 (4H, m), 8.70 (1H, d). Intermediate 40: 4-{3-[3-(difluoromethoxy)-4-formylphenyl]-LH-pyrazol-l- yl} benzonitrile

Prepared similar as described for intermediate 21 from intermediate 19 (0.25 g, 0.84 mmol) and intermediate 39 (0.22 g, 0.88 mmol). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.18 g, 63 %): 1H NMR (500 MHz, DMSO) 7.32 - 7.68 (2H, m), 7.9 - 7.98 (2H, m), 8 - 8.07 (3H, m), 8.18 (2H, d), 8.84 (1H, d), 10.29 (1H, s).

Intermediate 41: 2-(difluoromethoxy)-4-(lH-pyrazol-3-yl)benzaldehyde

4-bromo-2-(difluoromethoxy)benzaldehyde (7 g, 27.89 mmol) was added to (U/-pyrazol-3- yl)boronic acid (4.68 g, 41.83 mmol), 1,1'- Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (2.277 g, 2.79 mmol) and potassium phosphate, tribasic (17.76 g, 83.66 mmol) in N,N- dimethylformamide (50 mL) and water (20 mL) at 17°C over a period of 1 minute under nitrogen. The resulting solution was stirred at 100 °C for 5 hours. The reaction mixture was then diluted with ethyl acetate (100 mL), washed successively with water (1 x 100 mL) and brine (lx 100 mL), then dried (sodium sulfate), filtered and concentrated. Flash C-18 chromatography of the residue using acetonitrile in water (gradient elution, 0 to 70%) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (3.20 g, 48 %): 1H NMR (400 MHz, DMSO, 26°C) 5 6.93 (1H, t), 7.47 (2H, t), 7.81 (1H, s), 7.88 (3H, d), 10.26 (1H, s), 13.23 (1H, s). Intermediate 42: 2-{3-[3-(difluoromethoxy)-4-formylphenyl]-LH-pyrazol-l- yl} benzonitrile

Pyridine (0.136 mL, 1.68 mmol) was added to 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (385 mg, 1.68 mmol, CAS RN 214360-48-2), intermediate 41 (200 mg, 0.84 mmol) and copper(II) acetate (305 mg, 1.68 mmol) in AA-dimethylacetamide (5mL) at rt under air and stirred at 38 °C for 16 hours under air. The reaction mixture was then filtered through celite and purified by flash Cl 8 chromatography using acetonitrile in water (gradient elution, 0 to 100 %). Appropriate fractions were concentrated and concentrated providing the title compound as a white solid (180 mg, 63 %): 1H NMR (300 MHz, DMSO-d6) 5 7.34 (d, J = 2.6 Hz, 1H), 7.61 (td, J = 7.4, 1.5 Hz, 1H), 7.84 -8.10 (m, 6H), 8.59 (d, J = 2.6 Hz, 1H), 10.27 (s, 1H).

Intermediate 43: 2-(difluoromethoxy)-4-[l-(4-fluorophenyl)-lH-pyrazol-3- yl] benzaldehyde

Pyridine (0.319 mL, 3.95 mmol) was added to intermediate 41 (470 mg, 1.97 mmol), (4- fluorophenyl)boronic acid (552 mg, 3.95 mmol) and copper(II) acetate (717 mg, 3.95 mmol) in AA-dimethylacetamide (8 mL). The resulting mixture was stirred at rt for 15 hours under air. The reaction mixture was then diluted with ethyl acetate (50 mL), washed successively with water (1 x 50 mL) and brine (1 x 50 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-20 %) followed by concentration of the appropriate fractions gave the title compound as a yellow solid (590 mg, 90 %): 1H NMR (400 MHz, CDC13, 26°C) 5 6.58-6.96 (2H, m), 7.17-7.25 (2H, m), 7.75 (1H, dd), 7.76-7.79 (1H, m), 7.81 (1H, d), 7.84 (1H, dt), 7.96 (1H, d), 8.01 (1H, d), 10.43 (1H, s).

Intermediate 44: 2-(difluoromethoxy)-4-[l-(3-fluorophenyl)-LH-pyrazol-3- yl] benzaldehyde

Pyridine (0.17 mL, 2.10 mmol) was added to (3-fluorophenyl)boronic acid (294 mg, 2.10 mmol), intermediate 41 (250 mg, 1.05 mmol) and copper(II) acetate (381 mg, 2.10 mmol) in -di methyl acetamide (3 mL) at rt under air. The resulting mixture was stirred at rt for 16 h under air. The reaction mixture was filtered through celite and the solids washed with methanol and partly concentrated. The residue was purified by flash C18 chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were concentrated to afford the title compound as a yellow solid (220 mg, 63 %): 1H NMR (400 MHz, CDC13) 5 6.59-6.99 (2H, m), 7.01-7.09 (1H, m), 7.47 (1H, td), 7.52-7.61 (2H, m), 7.79-7.87 (2H, m), 8.01 (2H, dd), 10.43 (1H, s).

Intermediate 45: 2-(difluoromethoxy)-4-[l-(2-methylphenyl)-lH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 44 using intermediate 41 (0.20 g, 0.84 mmol) and (2-methylphenyl)boronic acid (0.228 g, 1.68 mmol). The residue was purified by flash Cl 8 chromatography, elution gradient 0 to 80% MeCN in water. Pure fractions were concentrated to afford the title compound as a yellow solid (220 mg, 63 %): m/z (ES+) [M+H]⁺ = 329. Intermediate 46: 4-{3-[3-(difluoromethoxy)-4-formylphenyl]-lH-pyrazol-l-yl}-3- methylbenzonitrile

Prepared similar as described for intermediate 44 using intermediate 41 (0.20 g, 0.84 mmol) and (4-cyano-2-methylphenyl)boronic acid (0.27 g, 1.68 mmol), m/z (ES+) [M+H]⁺ = 354.

Intermediate 47: 2-(difluoromethoxy)-4-[l-(4-methoxyphenyl)-lH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 43 from intermediate 41 (0.20 g, 0.84 mmol) and (4-methoxyphenyl)boronic acid (0.25 g, 1.68 mmol) providing the title compound as a yellow solid (0.21 g, 73 %): 1H NMR (300 MHz, CDC13) 5 3.89 (3H, s), 6.53-7.03 (3H, m), 7.04 (1H, d), 7.66-7.72 (2H, m), 7.79-7.86 (2H, m), 7.92 (1H, d), 8.00 (1H, d), 10.42 (1H, s).

Intermediate 48: 2-(difluoromethoxy)-4-{l-[4-(difluoromethoxy)phenyl]-lH-pyrazol-3- yl} benzaldehyde

Prepared similar as described for intermediate 43 from intermediate 41 (0.20 g, 0.84 mmol) and [4-(difluoromethoxy)phenyl]boronic acid (0.32 g, 1.68 mmol) providing the title compound as a yellow solid (0.17 g, 53 %): 1H NMR (300 MHz, CDC13) 5 6.33-7.02 (3H, m), 7.28 (1H, d), 7.30 (1H, s), 7.79 (1H, d), 7.81 (1H, d), 7.82 (1H, d), 7.83-7.87 (1H, m), 7.99 (1H, d), 8.02 (1H, d), 10.43 (1H, s).

Intermediate 49: 3-{3-[3-(difluoromethoxy)-4-formylphenyl]-LH-pyrazol-l- yl} benzonitrile

Prepared similar as described for intermediate 44 from intermediate 41 (0.20 g, 0.84 mmol) and (3-cyanophenyl)boronic acid (0.25 g, 1.68 mmol) providing the title compound as a yellow solid (0.22 g, 77 %): 1H NMR (300 MHz, DMSO) 5 7.27-7.84 (m, 4H), 7.9-7.96 (m, 2H), 8.01 (d, J = 8.2 Hz, 1H), 8.32 (ddd, J = 8.1, 2.4, 1.3 Hz, 1H), 8.45 (t, J = 1.9 Hz, 1H), 8.78 (d, J = 2.7 Hz, 1H), 10.29 (s, 1H).

Intermediate 50: 2-(difluoromethoxy)-4-[l-(2-fluorophenyl)-LH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 44 from intermediate 41 (0.30 g, 1.26 mmol) and 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.839 g, 3.78 mmol) providing the title compound as a yellow solid (0.30 g, 72 %): 1H NMR (400 MHz, DMSO) 5 0.93 (3H, s), 0.95-1.08 (1H, m), 1.45 (1H, s), 1.6-1.74 (3H, m), 1.83-1.97 (2H, m), 2.79 (1H, d), 3.01 (1H, d), 3.54 (2H, d), 7.06-7.23 (2H, m), 7.27 (OH, s), 7.51-7.63 (2H, m), 7.73 (1H, d), 7.77-7.87 (3H, m), 8.67 (1H, d).

Intermediate 51: 2-(difluoromethoxy)-4-{l-[4-(3-methyloxetan-3-yl)phenyl]-lH-pyrazol- 3-yl} benzaldehyde

Prepared similar as described for intermediate 44 from intermediate 41 (0.30 g, 1.26 mmol) and 4,4,5,5-tetramethyl-2-[4-(3-methyloxetan-3-yl)phenyl]-l,3,2-dioxaborolane (0.244 g, 0.84 mmol, CAS RN 1453860-99-5) providing the title compound as a white solid, containing 50 % of residual 4,4,5,5-tetramethyl-2-[4-(3-methyloxetan-3-yl)phenyl]-l,3,2-dioxaborolane as judged by NMR, which was used as such in the next step (0.30 g). m/z (ES+) [M+H]⁺ = 401.

Intermediate 52: 2-(cyclopropyloxy)-4-( 1-phenyl-l //-pyr:izol-3-yl)benzaldehyde l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (66.1 mg, 0.08 mmol) was added to l-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-UT- pyrazole (160 mg, 0.59 mmol, CAS RN 1002334-13-5), 4-bromo-2- (cyclopropyloxy)benzaldehyde (130 mg, 0.54 mmol, from step 2 of intermediate 15) and caesium carbonate (351 mg, 1.08 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) at rt under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours, then filtered through celite. The filtrate was diluted with ethyl acetate (50 mL), washed successively with water (1 x 50 mL) and brine (1 x 50 mL), then dried (sodium sulfate), filtered and concentrated.

Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-15 %), followed by concentration of the appropriate fractions gave the title compound as a white solid (88 mg, 54 %): m/z (ES+) [M+H]⁺ = 305.

Intermediate 53: 3-|4-(chloromethyl)-3-cyclopropylphenyl|-l-phenyl-l//-pyrazole

Step . methyl 2-cyclopropyl-4-(l-phenyl-U/-pyrazol-3-yl)benzoate

Tetrakis(triphenylphosphine)palladium(0) (272 mg, 0.24 mmol) was added to l-phenyl-3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-U7-pyrazole (551 mg, 2.04 mmol, CAS RN 1002334-13-5), methyl 4-bromo-2-cyclopropylbenzoate (400 mg, 1.57 mmol, from intermediate 16, step 1) and caesium carbonate (1022 mg, 3.14 mmol) in 1,4-di oxane (20 mL) and water (2 mL) at rt under nitrogen. The resulting mixture was stirred at 100 °C for 16 hours, then filtered through celite. The filtrate was diluted with ethyl acetate (50 mL), washed successively with water (1 x 50 mL) and brine (1 x 50 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0-15 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (400 mg, 80 %): 1H NMR (300 MHz, DMSO-d6) 5 0.74-0.89 (m, 2H), 0.94-1.09 (m, 2H), 2.64 (tt, J = 8.4, 5.3 Hz, 1H), 3.85 (s, 3H), 7.16 (d, J = 2.6 Hz, 1H), 7.29-7.38 (m, 1H), 7.46-7.58 (m, 3H), 7.76-7.85 (m, 2H), 7.86- 7.96 (m, 2H), 8.59 (d, J = 2.7 Hz, 1H).

Step 2 3-[4-(chloromethyl)-3-cyclopropylphenyl]-l-phenyl-177-pyrazole (intermediate 53)

Lithium aluminium hydride (83 mg, 2.20 mmol) was added to methyl 2-cyclopropyl-4-(l- phenyl-U/-pyrazol-3-yl)benzoate (350mg, 1.10 mmol) in THF (5 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0 °C for 1 hours. The reaction mixture was then quenched with water (138ul), filtered through a pad of celite pad and concentrated. To the residue (colorless oil) dissolved in acetonitrile (5 mL) and N, A^f-di methyl form am ide (0.03 mL, 0.40 mmol) was added thionyl chloride (0.115 mL, 1.58 mmol) at 0°C under nitrogen, then stirred at rt for 2 h. The reaction mixture was then concentrated and the residue applied to a silica gel column. Flash chromatography using ethyl acetate in petroleum ether (gradient elution, 0- 25 %) followed by concentration of the appropriate fractions gave the title compound as a colourless oil (200 mg, 59 %). m/z (ES+) [M+H]⁺ = 309.

Intermediate 54: 2-(difl uoromethoxy )-4-(4-methyl-l -phenyl- TH-pyrazol-3- yl)benzaldehyde

Prepared similar as described for intermediate 21 from intermediate 19 (0.25 g, 0.84 mmol) and 3-bromo-4-methyl-l-phenyl-177-pyrazole (0.219 g, 0.92 mmol, CAS RN 1700661-39-7).

Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 12-20 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.14 g, 51 %): 1H NMR (500 MHz, DMSO) 2.35 (3H, d), 7.31 - 7.65 (4H, m), 7.75 (1H, d), 7.83 - 7.92 (3H, m), 7.96 (1H, d), 8.48 (1H, d), 10.30 (1H, s).

Intermediate 55: 4-{3-[3-(difluoromethoxy)-4-formylphenyl]-4-methyl-lH-pyrazol-l- yl} benzonitrile

Step 1: 4-(3-bromo-4-methyl-lH-pyrazol-l-yl)benzonitrile

A stirred mixture of 3-bromo-4-methyl-lH-pyrazole (0.5 g, 3.11 mmol), 4-fluorobenzonitrile (0.414 g, 3.42 mmol) and cesium carbonate (1.518 g, 4.66 mmol) in A, A-di methyl form am ide (3 mL) was heated at 50°C for 2 hours, then allowed to cool to rt and partitioned between ethyl acetate (25 mL) and water (20 mL). The organic layer was washed successively with water (2 x 20 mL) and brine (1 x 10 mL), then dried (sodium sulfate), filtered and concentrated to provide the crude title compound as a white solid which was used in the next step without further purification (0.79 g): 1H NMR (500 MHz, DMSO) 2.04 (3H, d), 7.93 - 8 (4H, m), 8.55 (1H, d).

Step 2'. 4-{3-[3-(difluoromethoxy)-4-formylphenyl]-4-methyl-U/-pyrazol-l-yl (benzonitrile (intermediate 55).

Prepared similar as described for intermediate 21 from intermediate 19 (0.25 g, 0.84 mmol) and 4-(3-bromo-4-methyl-U/-pyrazol-l-yl)benzonitrile (0.231 g, 0.88 mmol). Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 12- 20 %) followed by concentration of the appropriate fractions gave the title compound as a white solid (0.21 g, 71 %): 1H NMR (500 MHz, DMSO) 2.35 (3H, d), 7.49 (1H, t), 7.77 (1H, d), 7.87 (1H, dt), 7.97 (1H, d), 7.99 - 8.04 (2H, m), 8.09 - 8.13 (2H, m), 8.65 (1H, d), 10.31 (1H, s).

Intermediate 56: 2-(difl uoromethoxy )-4-(5-methyl-l -phenyl- lH-pyrazol-3- yl)benzaldehyde

Step 1: 2-(difluoromethoxy)-4-(5-methyl-lH-pyrazol-3-yl)benzaldehyde

4-bromo-2-(difluoromethoxy)benzaldehyde (400 mg, 1.59 mmol) was added to (5-methyl- U/-pyrazol-3-yl)boronic acid (301 mg, 2.39 mmol), l,l'-Bis(diphenylphosphino) ferrocenedichloropalladium (II) dichloromethane adduct (130 mg, 0.16 mmol) and potassium phosphate, tribasic (1015 mg, 4.78 mmol) in methyl form am ide (1 mL) and water (0.4 mL) at 17°C over a period of 1 minute under nitrogen. The resulting solution was stirred at 100 °C for 2 hours, then allowed to cool to rt. The reaction mixture was then diluted with ethyl acetate (50 mL), washed successively with water (1 x 50 mL), brine (1 x 50 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0 to 60 %) followed by concentration of the appropriate fraction gave the title compound as a white solid (270 mg, 67.2 %): 1H NMR (300 MHz, DMSO, 26°C) 5 2.30 (3H, s), 6.65 (1H, s), 7.47 (1H, t), 7.74 (1H, s), 7.81 (1H, d), 7.87 (1H, d), 10.25 (1H, s), 12.91 (1H, s).

Step 2 2-(difluoromethoxy)-4-(5-methyl-l-phenyl-U/-pyrazol-3-yl)benzaldehyde (intermediate 56).

Pyridine (0.154 mL, 1.90 mmol) was added to 2-(difluoromethoxy)-4-(5-methyl-lH-pyrazol- 3-yl)benzaldehyde (240 mg, 0.95 mmol), phenylboronic acid (232 mg, 1.90 mmol) and Copper(II) acetate (346 mg, 1.90 mmol) in A /f-di methyl acetamide (3 mL), then stirred at rt for 15 h. The resulting mixture was stirred at RT for 15 hours under air. The reaction mixture was then diluted with ethyl acetate (50 mL), washed successively with with water (1 x 50 mL) and brine (50 mL), then dried (sodium sulfate), filtered and concentrated. Flash chromatography of the residue using ethyl acetate in petroleum ether (gradient elution, 0 to 20 %) followed by concentration of the appropriate fraction gave the title compound as a pale yellow solid (250 mg, 80 %): 1H NMR (300 MHz, DMSO, 26°C) 5 2.39 (3H, d), 6.97 (1H, d), 7.44-7.53 (2H, m), 7.54-7.58 (1H, m), 7.59 (1H, dd), 7.61-7.65 (2H, m), 7.80 (1H, d), 7.85-7.95 (2H, m), 10.28 (1H, s).

Intermediate 57: 2-(difluoromethoxy)-4-(l-methyl-5-phenyl-lH-pyrazol-3- yl)benzaldehyde

Step . 3-bromo-l-methyl-5-phenyl-U/-pyrazole

A degassed (argon) mixture of phenylboronic acid (152 mg, 1.25 mmol), 3, 5 -dibromo- 1- methyl-lH-pyrazole (300 mg, 1.25 mmol), potassium carbonate (432 mg, 3.13 mmol) and Pd(dppf)C12*DCM (102 mg, 0.13 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated to 100°C for 90 minutes. The mixture was allowed to cool to rt, diluted with ethyl acetate (20 mL) and washed with brine (10 mL), then dried filtered and concentrated. The residue was dissolved in a small volume of di chloromethane and applied to a silica gel column. Elution using ethyl acetate in heptane (stepwise gradient elution, 5-10 %) followed by concentration of the appropriate fractions gave the title compound, containing ~20 % of l-methyl-3,5- diphenyl-UT-pyrazole, as a colorless oil (0.14 g, 47 %): 1H NMR (500 MHz, DMSO) 3.81 (3H, s), 6.56 (1H, s), 7.44 - 7.57 (5H, m). This material was used as such in the next step.

Step 2 2-(difluoromethoxy)-4-(l-methyl-5-phenyl-U/-pyrazol-3-yl)benzaldehyde (intermediate 57)

To intermediate 19 (194 mg, 0.65 mmol), XPhos Pd G3 (24.99 mg, 0.03 mmol) and potassium carbonate (204 mg, 1.48 mmol) was added a solution of 3-bromo-l-methyl-5- phenyl-UT-pyrazole (140mg, 0.59 mmol) in 1,4-dioxane (6 mL) followed by water (2 mL), then degassed by bubbling argon. The reaction mixture was then stirred at 85 °C for 1.5 h, allowed to cool, then diluted with ethyl acetate (25 mL), washed with brine (1 x 15 mL), dried (sodium sulfate), filtered and concentrated. The residue was dissolved in a small volume of dichloromethane and applied to a silica gel column. Elution using ethyl acetate in heptane (stepwise gradient elution, 12-20 %) followed by concentration of the appropriate fractions gave the title compound as a slight yellowish solid (160 mg, 83%): 1H NMR (500 MHz, DMSO) 3.96 (3H, s), 7.14 (1H, s), 7.32 - 7.67 (6H, m), 7.81 (1H, t), 7.85 - 7.95 (2H, m), 10.27 (1H, s).

Intermediate 58: 2-(difluoromethoxy)-4-(l-methyl-3-phenyl-lH-pyrazol-5- yl)benzaldehyde

Step 1 : 4-(3 -bromo- 1 -methyl- U/-pyrazol-5-yl)-2-(difluoromethoxy)benzaldehyde

To intermediate 19 (236 mg, 0.79 mmol), Pd(dppf)C12*DCM (50 mg, 0.06 mmol) and carbonate (288 mg, 2.08 mmol) was added a solution of 3,5-dibromo-l-methyl-lH-pyrazole (200 mg, 0.83 mmol, CAS RN 1361019-05-7) in 1,4-dioxane (6 mL) followed by water (1.5 mL), then degassed by bubbling argon. The reaction mixture was then stirred at 95 °C for 1 h, allowed to cool, then diluted with ethyl acetate (20 mL), washed with brine (1 x 10 mL), dried (sodium sulfate), filtered and concentrated. The residue was dissolved in a small volume of dichloromethane and applied to a silica gel column. Elution using ethyl acetate in heptane (stepwise gradient elution, 12-20 %) followed by concentration of the appropriate fractions gave the title compound as a colorless syrup (0.12 g, 43 %): 1H NMR (500 MHz, DMSO)

3.89 (3H, s), 6.79 (1H, s), 7.27 - 7.61 (2H, m), 7.63 (1H, ddd), 7.95 (1H, d), 10.30 (1H, s).

Step 2 2-(difluoromethoxy)-4-(l-methyl-3-phenyl-U/-pyrazol-5-yl)benzaldehyde (intermediate 58)

To phenylboronic acid (48.6 mg, 0.40 mmol), XPhos Pd G3 (14.06 mg, 0.02 mmol) and potassium carbonate (115 mg, 0.83 mmol) was added a solution of 4-(3 -bromo- 1 -methyl- H- pyrazol-5-yl)-2-(difluoromethoxy)benzaldehyde (HOmg, 0.33 mmol) in 1,4-dioxane (3 mL) followed by water (1.0 mL), then degassed by bubbling argon. The reaction mixture was then stirred at 85 °C for 1 h, allowed to cool, then diluted with ethyl acetate (15 mL), washed with brine (2 mL), dried (sodium sulfate), filtered and concentrated. The residue was dissolved in a small volume of di chloromethane and applied to a silica gel column. Elution using ethyl acetate in heptane (stepwise gradient elution, 12-20 %) followed by concentration of the appropriate fractions gave the title compound as a colorless syrup (90 mg, 83 %): 1H NMR (500 MHz, DMSO) 3.99 (3H, s), 7.12 (1H, s), 7.29 - 7.66 (5H, m), 7.70 (1H, ddd), 7.81 -

7.89 (2H, m), 7.98 (1H, d), 10.32 (1H, d).

Intermediate 59: 4-{3-[3-(difluoromethoxy)-4-formylphenyl]-l-methyl-lH-pyrazol-5- yl} benzonitrile

Prepared similar as described for intermediate 57 from intermediate 19 (0.169 g, 0.57 mmol) and 4-(3-bromo-l-methyl-l/7-pyrazol-5-yl)benzonitrile (0.135 g, 0.52 mmol, prepared from (4-cyanophenyl)boronic acid and 3,5-dibromo-l-methyl-lH-pyrazole similar as described for intermediate 57, step 1). Slight yellow solid (0.11 g, 60 %): 1H NMR (500 MHz, DMSO) 3.99 (3H, s), 7.29 (1H, s), 7.47 (1H, t), 7.80 (1H, d), 7.84 - 7.87 (2H, m), 7.87 - 7.93 (2H, m), 8 - 8.06 (2H, m), 10.26 (1H, s).

Intermediate 60: 2-(difluoromethoxy)-4-{l-methyl-5-[6-(trifluoromethyl)pyridin-3-yl]- LH-pyrazol-3-y 1 } benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 19 (0.155 g, 0.52 mmol) and 5-(3-bromo-l-methyl-l/7-pyrazol-5-yl)-2-(trifluoromethyl)pyridine (0.145 g, 0.47 mmol, prepared from [6-(trifluoromethyl)pyridin-3-yl]boronic acid and 3,5-dibromo-l-methyl-lH- pyrazole similar as described for intermediate 57, step 1). White solid (0.145 g, 77 %): 1H NMR (500 MHz, DMSO) 4.03 (3H, s), 7.31 - 7.64 (2H, m), 7.81 (1H, d), 7.87 - 7.96 (2H, m), 8.10 (1H, dd), 8.39 (1H, dd), 9.06 (1H, d), 10.27 (1H, s).

Intermediate 61: 2-(difluoromethoxy)-4-(l-ethyl-5-phenyl-lH-pyrazol-3-yl)benzaldehyde Prepared similar as described for intermediate 57 from intermediate 19 (0.380 g, 1.27 mmol) and 3-bromo-l-ethyl-5-phenyl-l/7-pyrazole (0.320 g, 1.27 mmol, prepared from phenylboronic acid and 3,5-dibromo-l-ethyl-U7-pyrazole similar as described for intermediate 57, step 1). Slight yellow viscous oil (0.230 g, 53 %): 1H NMR (500 MHz, DMSO) 1.37 (3H, t), 4.22 (2H, q), 7.07 (1H, s), 7.31 - 7.64 (6H, m), 7.79 - 7.83 (1H, m), 7.90 (2H, d), 10.26 (1H, s).

Intermediate 62: 2-(difluoromethoxy)-4-[5-(6-fluoropyridin-2-yl)-l-methyl-lZ/-pyrazol- 3-yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 19 (0.196 g, 0.66 mmol) and 2-(3-bromo-l-methyl-l/7-pyrazol-5-yl)-6-fluoropyridine (0.140 g, 0.55 mmol, prepared from (6-fluoropyridin-2-yl)boronic acid and 5-dibromo-l-methyl-lH-pyrazole similar as described for intermediate 57, step 1). White solid (0.080 g, 42 %): 1H NMR (500 MHz, DMSO) 4.23 (3H, s), 7.25 (1H, dd), 7.32 - 7.65 (2H, m), 7.81 (1H, s), 7.86 (1H, dd), 7.88 - 7.95 (2H, m), 8.17 (1H, q), 10.27 (1H, s).

Intermediate 63: 2-(difluoromethoxy)-4-[l-(2-methoxyethyl)-5-phenyl-lZ/-pyrazol-3- yl] benzaldehyde

Step . 3, 5 -dibromo- 1 -(2 -methoxyethyl)- l7/-pyrazole A mixture of 3,5-dibromo-U/-pyrazole (0.694 g, 3.07 mmol), l-bromo-2-methoxy ethane (0.641 g, 4.61 mmol) and cesium carbonate (2.00 g, 6.15 mmol) in A A i methyl form am ide (4 mL) was stirred over the weekend after which a precipitate formed. The precipitate was partitioned between ethyl acetate (40 mL) and water (40 mL). The water layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed successively with water (3 x 30 mL) and brine (1 x 20 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 5-10 %) followed by concentration of the appropriate fractions gave the title compound as a colorless oil (0.73 g, 84 %): 1H NMR (500 MHz, DMSO) 3.21 (3H, s), 3.67 (2H, t), 4.26 (2H, t), 6.64 (1H, s).

Step 2'. 3-bromo-l-(2-methoxyethyl)-5-phenyl-lJ/-pyrazole

Prepared similar as described in step 1 for intermediate 57 from 3,5-dibromo-l-(2- methoxy ethyl)- UT-pyrazole (0.700 g, 2.47 mmol) and phenylboronic acid (0.301 g, 2.47 mmol). Colorless oil (0.50 g, 73 %): 1H NMR (500 MHz, DMSO) 3.14 (3H, s), 3.68 (2H, t), 4.19 (2H, t), 6.51 (1H, s), 7.47 - 7.55 (5H, m).

Step 3 : 2-(difluoromethoxy)-4-[ 1 -(2-methoxyethyl)-5-phenyl- U/-pyrazol-3 -yl]benzaldehyde (intermediate 63).

Prepared similar as described for intermediate 57 from intermediate 19 (0.530 g, 1.78 mmol) and 3-bromo-l-(2-methoxyethyl)-5-phenyl-U/-pyrazole (0.500 g, 1.78 mmol). Yellow viscous oil (0.305 g, 46 %): 1H NMR (500 MHz, DMSO) 3.15 (3H, s), 3.77 (2H, t), 4.32 (2H, t), 7.07 (1H, s), 7.3 - 7.64 (7H, m), 7.81 (1H, s), 7.91 (2H, d), 10.27 (1H, s).

Intermediate 64: 2-(difluoromethoxy)-4-[5-(5,6-difluoropyridin-3-yl)-l-methyl-lH- pyr azol-3-yl] benzaldehyde Prepared similar as described for intermediate 57 from intermediate 19 (0.170 g, 0.57 mmol) and 5-(3-bromo-l-methyl-U/-pyrazol-5-yl)-2,3-difluoropyridine (0.130 g, 0.47 mmol, prepared from 5,6-difluoropyridin-3-yl)boronic acid and 5-dibromo-l -methyl- IH-pyrazole similar as described for intermediate 57, step 1). White solid (0.085 g, 49 %): 1H NMR (500 MHz, DMSO) 3.99 (3H, s), 7.29 (1H, s), 7.47 (1H, t), 7.79 (1H, d), 7.88 (1H, dt), 7.92 (1H, d), 8.35 (1H, t), 8.42 (1H, ddd), 10.26 (1H, s).

Intermediate 65: 5- {3-[3-(difluoromethoxy )-4-formylphenyl]-l -methyl- TH-pyrazol-5- y 1} pyridine-2-carbonitrile

Prepared similar as described for intermediate 57 from intermediate 19 (0.068 g, 0.23 mmol) and 5-(3-bromo-l-methyl-U/-pyrazol-5-yl)pyridine-2-carbonitrile (0.050 g, 0.19 mmol, prepared from (6-cyanopyridin-3-yl)boronic acid and 5-dibromo-l -methyl- IH-pyrazole similar as described for intermediate 57, step 1). The title compound was used as a crude product directly in the next step, m/z (ES+) [M+H]⁺ = 355.

Intermediate 66: 2-(difluoromethoxy)-4-[ l-methyl-5-(6-methylpyridin-3-yl)-l//-pyrazol- 3-yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 19 (0.182 g, 0.61 mmol) and 5-(3-bromo-l-methyl-U/-pyrazol-5-yl)-2-methylpyridine (0.140 g, 0.56 mmol, prepared from (6-methylpyri din-3 -yl)boronic acid and 5-dibromo-l-methyl-lH-pyrazole similar as described for intermediate 57, step 1). White solid (0.115 g, 60 %): 1H NMR (500 MHz, DMSO) 2.55 (3H, s), 3.95 (3H, s), 7.20 (1H, s), 7.3 - 7.66 (2H, m), 7.80 (1H, s), 7.86 - 7.93 (2H, m), 7.95 (1H, dd), 8.67 - 8.71 (1H, m), 10.26 (1H, s). Intermediate 67: 2-(difluoromethoxy)-4-[l-ethyl-5-(6-fluoropyridin-2-yl)-LH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 19 (0.358 g, 1.20 mmol) and 2-(3-bromo-l-ethyl-l/7-pyrazol-5-yl)-6-fluoropyridine (0.270 g, 1.00 mmol, prepared from (6-fluoropyridin-2-yl)boronic acid and 3,5-dibromo-l-ethyl-U7-pyrazole similar as described for intermediate 57, step 1). White solid (0.09 g, 25 %): 1H NMR (500 MHz, DMSO) 1.43 (3H, t), 4.68 (2H, q), 7.27 (1H, dd), 7.34 - 7.66 (2H, m), 7.83 (1H, s), 7.88 (1H, dd), 7.93 (2H, d), 8.19 (1H, q), 10.28 (1H, s).

Intermediate 68: 2-(difluoromethoxy)-4-{l-ethyl-5-[6-(trifluoromethyl)pyridin-3-yl]-lH- pyrazol-3-yl} benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 19 (0.132 g, 0.44 mmol) and 5-(3-bromo-l-ethyl-l/7-pyrazol-5-yl)-2-(trifluoromethyl)pyridine (0.135 g, 0.42 mmol, prepared from [6-(trifluoromethyl)pyridin-3-yl]boronic acid and 3,5-dibromo-l-ethyl-lZ7- pyrazole similar as described for intermediate 57, step 1). Colorless solid (0.130 g, 75 %): 1H NMR (500 MHz, DMSO) 1.40 (3H, t), 4.29 (2H, q), 7.28 - 7.69 (2H, m), 7.83 (1H, s), 7.89 - 7.97 (2H, m), 8.11 (1H, d), 8.34 (1H, dd), 9.01 (1H, d), 10.28 (1H, s).

Intermediate 69: 2-(difluoromethoxy)-4-[5-(5,6-difluoropyridin-3-yl)-l-ethyl-lH- pyr azol-3-yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 19 (0.125 g, 0.42 mmol) and 5-(3-bromo-l-ethyl-U/-pyrazol-5-yl)-2,3-difluoropyridine (0.115 g, 0.40 mmol, prepared from 5,6-difluoropyridin-3-yl)boronic acid and 3,5-dibromo-l-ethyl-U/-pyrazole similar as described for intermediate 57, step 1). White solid (0.080 g, 53 %): 1H NMR (500 MHz, DMSO) 1.38 (3H, t), 4.26 (2H, q), 7.24 (1H, s), 7.49 (1H, t), 7.80 (1H, d), 7.86 - 7.96 (2H, m), 8.30 (1H, t), 8.34 - 8.42 (1H, m), 10.27 (1H, s).

Intermediate 70: 2-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzaldehyde

A mixture of 4-bromo-2-cyclopropylbenzaldehyde (1.00 g, 4.44 mmol, prepared as described for intermediate 5, step 3), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.297 g, 5.11 mmol), potassium acetate (1.308 g, 13.33 mmol) and Pd(dppf)cl2-DCM (0.181 g, 0.22 mmol) in 1,4-di oxane (30 mL) was degassed with argon, then sealed and heated under stirring at 100 °C for 2 h. The resulting reaction mixture was then allowed to cool to rt and was filtered through celite. The filter cake was washed with dixane and ethyl acetate and the filtrate was concentrated. Chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 5-10 %) followed by concentration of the appropriate fractions gave the title compound as a slight yellow solid (1.1 g, 91 %): 1H NMR (500 MHz, DMSO) 0.71 - 0.78 (2H, m), 1 - 1.09 (2H, m), 1.30 (12H, s), 2.71 (1H, tt), 7.39 (1H, s), 7.64 (1H, dd), 7.77 (1H, d), 10.57 (1H, s).

Intermediate 71: 2-cyclopropyl-4-( 1 -met liyl-5-plien l-l//-pyr:izol-3- l (benzaldeh de

Prepared similar as described for intermediate 57 from intermediate 70 (0.172 g, 0.63 mmol) and 3-bromo-l-methyl-5-phenyl-l/7-pyrazole (0.190 g, 0.60 mmol). Colorless gum (0.130 g, 72 %): 1H NMR (500 MHz, DMSO) 0.82 - 0.93 (2H, m), 1.01 - 1.11 (2H, m), 2.81 (1H, tt), 3.93 (3H, s), 7.10 (1H, s), 7.46 - 7.51 (1H, m), 7.52 - 7.57 (3H, m), 7.59 - 7.63 (2H, m), 7.83 (2H, d), 10.50 (1H, s).

Intermediate 72: 2-cyclopropyl-4-( l-ethyl-5-phenyl-l //-pyr:izol-3-yl)benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 70 (0.171 g, 0.63 mmol) and 3-bromo-l-ethyl-5-phenyl-l/7-pyrazole (0.200 g, 0.60 mmol prepared from phenylboronic acid and 3,5-dibromo-l-ethyl-U7-pyrazole similar as described for intermediate 57, step 1). Slight yellow solid (0.140 g, 74 %): 1H NMR (500 MHz, DMSO) 0.82 - 0.9 (2H, m), 1.03 - 1.11 (2H, m), 1.36 (3H, t), 2.81 (1H, tt), 4.20 (2H, q), 7.05 (1H, s), 7.46 - 7.52 (1H, m), 7.52 - 7.59 (5H, m), 7.8 - 7.87 (2H, m), 10.50 (1H, s).

Intermediate 73: 2-cyclopropyl-4-[5-(5,6-difluoropyridin-3-yl)-l-ethyl-lH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 70 (0.099 g, 0.36 mmol) and 5-(3-bromo-l-ethyl-l/7-pyrazol-5-yl)-2,3-difluoropyridine (0.100 g, 0.35 mmol, prepared from 5,6-difluoropyridin-3-yl)boronic acid and 3,5-dibromo-l-ethyl-U7-pyrazole similar as described for intermediate 57, step 1). Slight yellow solid (0.075 g, 61 %): 1H NMR (500 MHz, DMSO) 0.86 (2H, ddd), 1.03 - 1.15 (2H, m), 1.36 (3H, t), 2.81 (1H, ddd), 4.23 (2H, q), 7.21 (1H, s), 7.56 (1H, s), 7.84 (2H, d), 8.28 (1H, t), 8.35 (1H, ddd), 10.51 (1H, s).

Intermediate 74: 2-cyclopropyl-4-[l-ethyl-5-(5-fluoropyridin-3-yl)-LH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 70 (0.122 g, 0.45 mmol) and 3-(3-bromo-l-ethyl-l/7-pyrazol-5-yl)-5-fluoropyridine (0.115 g, 0.43 mmol, prepared from (5-fluoropyridin-3-yl)boronic acid and 3,5-dibromo-l-ethyl-l/Z-pyrazole similar as described for intermediate 57, step 1). Colorless solid (0.11 g, 77 %): 1H NMR (500 MHz, DMSO) 0.82 - 0.92 (2H, m), 1.03 - 1.13 (2H, m), 1.37 (3H, t), 2.82 (1H, tt), 4.25 (2H, p), 7.25 (1H, s), 7.57 (1H, s), 7.85 (2H, d), 8.03 (1H, ddd), 8.67 (1H, t), 8.71 (1H, d), 10.51 (1H, s).

Intermediate 75: 2-cyclopropyl-4-[l-ethyl-5-(6-fluoropyridin-3-yl)-lH-pyrazol-3- yl] benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 70 (0.153 g, 0.56 mmol) and 5-(3-bromo-l-ethyl-l/7-pyrazol-5-yl)-2-fluoropyridine (0.145 g, 0.54 mmol, prepared from (6-fluoropyridin-3-yl)boronic acid and 3,5-dibromo-l-ethyl-U7-pyrazole similar as described for intermediate 57, step 1). Colorless solid (0.130 g, 72 %): 1H NMR (500 MHz, DMSO) 0.82 - 0.9 (2H, m), 1.03 - 1.12 (2H, m), 1.36 (3H, t), 2.81 (1H, tt), 4.19 (2H, q), 7.17 (1H, s), 7.39 (1H, dd), 7.56 (1H, s), 7.84 (2H, d), 8.21 (1H, td), 8.46 (1H, d), 10.50 (1H, s).

Intermediate 76: 2-cyclopropyl-4-{l-methyl-5-[6-(trifluoromethyl)pyridin-3-yl]-lH- pyrazol-3-yl} benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 70 (0.121 g, 0.44 mmol) and 5-(3-bromo-l-methyl-l/7-pyrazol-5-yl)-2-(trifluoromethyl)pyridine (0.135 g, 0.42 mmol, prepared from [6-(trifluoromethyl)pyridin-3-yl]boronic acid and 3,5-dibromo-l-methyl-lH- pyrazole similar as described for intermediate 57, step 1). Colorless solid (0.120 g, 74 %): 1H NMR (500 MHz, DMSO) 0.83 - 0.93 (2H, m), 1.05 - 1.13 (2H, m), 1.39 (3H, t), 2.83 (1H, tt), 4.28 (2H, q), 7.33 (1H, s), 7.59 (1H, s), 7.87 (2H, d), 8.10 (1H, d), 8.33 (1H, dd), 9.01 (1H, d), 10.52 (1H, s).

Intermediate 77: 2-cyclopropyl-4-{l-ethyl-5-[6-(trifluoromethyl)pyridin-3-yl]-lH- pyrazol-3-yl} benzaldehyde

Prepared similar as described for intermediate 57 from intermediate 70 (0.132 g, 0.44 mmol) and 5-(3-bromo-l-ethyl-l/7-pyrazol-5-yl)-2-(trifluoromethyl)pyridine (0.135 g, 0.42 mmol, prepared from [6-(trifluoromethyl)pyridin-3-yl]boronic acid and 3,5-dibromo-l-ethyl-l/Z- pyrazole similar as described for intermediate 57, step 1). Colorless solid (0.130 g, 75 %): 1H NMR (500 MHz, DMSO) 1.40 (3H, t), 4.29 (2H, q), 7.28 - 7.69 (2H, m), 7.83 (1H, s), 7.89 - 7.97 (2H, m), 8.11 (1H, d), 8.34 (1H, dd), 9.01 (1H, d), 10.28 (1H, s).

Intermediate 78: 2-(difluoromethoxy)-4-{5-methyl-l-[6-(trifluoromethyl)pyridin-3-yl]- 1 H-py razol-3-y 1 } benzaldehyde

Step . 5-(3 -bromo-5 -methyl- 177-pyrazol - 1 -yl)-2-(trifluoromethyl)pyridine

[6-(trifluoromethyl)pyridin-3-yl]boronic acid (0.831 g, 4.35 mmol), 3-bromo-5-methyl-UT- pyrazole (0.467 g, 2.90 mmol) and copper(II) acetate (0.790 g, 4.35 mmol) in dichloromethane (25 mL) and pyridine (0.69 g, 8.70 mmol) was stirred at rt overnight. The reaction mixture was worked up by extraction between EtOAc/DCM and NH4Cl(aq.)/25% NH3 (aq.). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was dissolved in a minimal volume of dichloromethane and applied to a silica gel column. Chromatography by using ethyl acetate in heptane (stepwise gradient, 10-17 %) followed by concentration of the pure fractions gave the title compound as an oil (0.16 g, 18 %): 1H NMR (500 MHz, DMSO) 2.43 (3H, d), 6.57 (1H, d), 8.10 (1H, dd), 8.32 (1H, dd), 9.02 (1H, d). Regioselectivity confirmed by NOE NMR.

Step 2'. 2-(difluoromethoxy)-4-{5-methyl-l-[6-(trifluoromethyl)pyridin-3-yl]-U/-pyrazol-3- yl (benzaldehyde (intermediate 78)

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.14 g, 0.47 mmol) and 5-(3-bromo-5-methyl-U/-pyrazol-l-yl)-2-(trifluoromethyl)pyridine (0.144 g, 0.47 mmol). White solid (0.13 g, 70 %): 1H NMR (500 MHz, DMSO) 2.52 (3H, d), 7.09 (1H, d), 7.48 (1H, t), 7.84 (1H, t), 7.93 (2H, d), 8.13 (1H, dd), 8.42 (1H, dd), 9.14 (1H, d), 10.28 (1H, s).

Intermediate 79: 2-(difluoromethoxy)-4-[l-(5,6-difluoropyridin-3-yl)-5-methyl-lH- pyr azol-3-yl] benzaldehyde

Step . 5-(3-bromo-5-methyl-l/7-pyrazol-l-yl)-2,3-difluoropyridine

Prepared similar as described for intermediate 78, step 1 from (5,6-difluoropyridin-3- yl)boronic acid (0.533 g, 3.35 mmol) and 3-bromo-5-methyl-l/7-pyrazole (0.40 g, 2.48 mmol). Oil (0.07 g, 10 %): 1H NMR (500 MHz, DMSO) 2.43 (3H, d), 6.57 (1H, d), 8.10 (1H, dd), 8.32 (1H, dd), 9.02 (1H, d).

Step 2: 2-(difluoromethoxy)-4-[l-(5,6-difluoropyridin-3-yl)-5-methyl-lZ7-pyrazol-3- yl]benzaldehyde (intermediate 79)

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.080 g, 0.27 mmol) and 5-(3-bromo-5-methyl-l/7-pyrazol-l-yl)-2,3-difluoropyridine (0.070 g, 0.26 mmol). White solid (0.045 g, 46 %): 1H NMR (500 MHz, DMSO) 2.44 (3H, d), 7.03 (1H, d), 7.47 (1H, t), 7.82 (1H, s), 7.89 - 7.94 (2H, m), 8.43 (1H, t), 8.51 (1H, ddd), 10.27 (1H, s).

Intermediate 80: 2-(difluoromethoxy)-4-(l-methyl-2-phenyl-lH-imidazol-5- yl)benzaldehyde

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.173 g, 0.58 mmol) and 5-bromo-l-methyl-2-phenyl-lJ7-imidazole (0.125 g, 0.53 mmol, CAS RN 71045- 44-8). White solid (0.115 g, 66%): 1H NMR (500 MHz, DMSO) 3.75 (3H, s), 7.29 - 7.67 (7H, m), 7.71 - 7.77 (2H, m), 7.95 (1H, d), 10.29 (1H, s). Intermediate 81: 2-(difluoromethoxy)-4-(l-methyl-2-phenyl-LH-imidazol-4- yl)benzaldehyde

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.21 g, 0.70 mmol) and 4-bromo-l-methyl-2-phenyl-lJ7-imidazole (0.167 g, 0.70 mmol, CAS RN 86119- 59-7). White solid (0.15 g, 65 %): 1H NMR (500 MHz, DMSO) 3.82 (3H, s), 7.31 - 7.62 (4H, m), 7.74 - 7.8 (3H, m), 7.83 (1H, dt), 7.87 (1H, d), 8.10 (1H, s), 10.23 (1H, s).

Intermediate 82: 2-(difluoromethoxy)-4-(4-phenyl-lH-imidazol-l-yl)benzaldehyde

A mixture of tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)s) (0.010 g, 0.01 mmol), di- tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[l,r-biphenyl]-2-yl)phosphane (0.013 g, 0.03 mmol) and in toluene (2.5 mL) and 1,4-dioxane (0.5 mL) was degassed, then sealed and heated to 120 °C for 3 min. The obtained solution was then cooled to rt and was quickly added 4-bromo-2-(difluoromethoxy)benzaldehyde (0.377 g, 1.5 mmol), 4-phenyl-UT- imidazole (0.260 g, 1.80 mmol) and tripotassium phosphate (0.637 g, 3.00 mmol) and the resulting mixture was degassed, sealed and stirred at 120°C for 3 hours. The reaction mixture was then allowed to cool to rt, partitioned between ethyl acetate (25 mL) and water (20 mL). The organic layer was washed with brine (5 mL), dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-50 %) followed by concentration of the appropriate fractions gave the title compound as an off-white solid (0.24 g, 51 %): 1H NMR (500 MHz, DMSO) 7.29 (1H, ddt), 7.35 - 7.67 (3H, m), 7.82 (1H, d), 7.84 - 7.92 (3H, m), 8.01 (1H, d), 8.52 (1H, d), 8.61 (1H, d), 10.26 (1H, d). Intermediate 83: 2-(difluoromethoxy)-4-(4-phenyl-LH-pyrazol-l-yl )benzaldehyde

A solution of tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)s) (0.055 g, 0.06 mmol) and di-tert-butyl(2',4',6'-triisopropyl-[l,r-biphenyl]-2-yl)phosphane (t-BuXPhos) (0.051 g, 0.12 mmol) in 1,4-di oxane (3 mL) was degassed, sealed and heated to 110°C for 3 minutes. The resulting solution was then cooled to rt and to the solution was quickly added 4-bromo-2- (difluoromethoxy)benzaldehyde (0.301 g, 1.2 mmol), 4-phenyl-lJT-pyrazole (0.208 g, 1.44 mmol) and cesium carbonate (0.782 g, 2.40 mmol), then degassed, sealed and heated to 110 °C for 3 h. The reaction mixture was then allowed to cool to rt, partitioned between ethyl acetate (25 mL) and water (20 mL). The organic layer was washed with brine (5 mL), dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-17 %) followed by concentration of the appropriate fractions gave the title compound as an off-white solid (0.23 g, 61 %): 1H NMR (500 MHz, DMSO) 7.27 - 7.35 (1H, m), 7.35 - 7.7 (3H, m), 7.73 - 7.83 (2H, m), 7.92 (1H, d), 7.96 - 8.05 (2H, m), 8.41 (1H, d), 9.24 (1H, d), 10.26 (1H, d).

Intermediate 84: 2-(difluoromethoxy)-4-[l-(4-fluorophenyl)-lH-imidazol-4- yl] benzaldehyde

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.20 g, 0.67 mmol) and 4-bromo-l-(4-fhiorophenyl)-17/-imidazole (0.162 g, 0.67 mmol, CAS RN 623577-59-3). White solid (0.080 g, 36 %): 1H NMR (500 MHz, DMSO) 7.19 - 7.63 (3H, m), 7.76 - 7.84 (3H, m), 7.89 (2H, d), 8.42 (1H, d), 8.59 (1H, d), 10.24 (1H, s).

Intermediate 85: 2-(difluoromethoxy)-4-(3-phenyl-l,2,4-oxadiazol-5-yl)benzaldehyde

Step . 2-(difluoromethoxy)-4-iodobenzoic acid

To a solution of methyl 2-hydroxy-4-iodobenzoate (2.78 g, 10 mmol) in 1 :1 acetonitrile-water (20 mL) was added portionwise potassium hydroxide (3.93 g, 70.00 mmol) then cooled (ice bath) and diethyl (bromodifluoromethyl)phosphonate (2.85 mL, 16.00 mmol) was added dropwise, while keeping the reaction mixture temperature around 20°C. The reaction mixture was stirred at rt overnight, then water and extracted with ethyl acetate. The aqueous phase was brought to pH 4 with IM HC1 and was extracted with ethyl acetate twice. The combined organic layers were dried (magnesium sulfate) filtered and concentrated. The residue was used as such in the next step without further purification. White solid (3.07 g): 1H NMR (500 MHz, DMSO) 7.21 (1H, t), 7.58 (1H, d), 7.65 (1H, dd), 7.76 (1H, dd), 13.31 (1H, s).

Step 2 [2-(difluoromethoxy)-4-iodophenyl]methanol

Borane dimethyl sulfide complex solution (0.960 mL, 10.13 mmol) was added dropwise to a solution of 2-(difluoromethoxy)-4-iodobenzoic acid (1.59 g, 5.06 mmol) in tetrahydrofurane (15 mL) and kept stirring at room temperature with a water bath overnight. The reaction mixture was quenched with aq. IM HC1, diluted with dichloromethane and passed through a phase separator. The organic phase was concentrated and was purified by column chromatography (0-60% EtOAc in Heptanes) gave the title compound as a white solid (1.292 g, 85 %): 1H NMR (500 MHz, CDC13) 4.70 (2H, s), 6.54 (1H, t), 7.22 (1H, dd), 7.46 (1H, q), 7.58 (1H, dd).

Step 3: 2-(difluoromethoxy)-4-iodobenzaldehyde

(2-(difluoromethoxy)-4-iodophenyl)methanol (1.292 g, 4.31 mmol) was dissolved in dichloromethane (50 mL) and manganese(IV) oxide (1.872 g, 21.53 mmol) was added, then the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated. The residue was redissolved in dichloromethane (25 mL) and manganese(IV) oxide (1.872 g, 21.53 mmol) was added and the reaction mixture was stirred another night. Additional manganese(IV) oxide (1.872 g, 21.53 mmol) was added and the reaction mixture was stirred at room temperature another night, then filtered through a pad of celite and concentrated. Column chromatography of the residue (0-50% EtOAc in Heptanes) gave the title compound (0.615 g, 47.9 %): 1H NMR (500 MHz, CDC13) 6.65 (1H, t), 7.61 - 7.64 (1H, m), 7.64 - 7.65 (1H, m), 7.69 - 7.76 (1H, m), 10.33 (1H, s).

Step 4: 2-(difluoromethoxy)-4-(3-phenyl-l,2,4-oxadiazol-5-yl)benzaldehyde (intermediate 85) A mixture of 3-phenyl-l,2,4-oxadiazole (36.5 mg, 0.25 mmol, CAS RN 5157-62-0), 2- (difluoromethoxy)-4-iodobenzaldehyde (149 mg, 0.50 mmol), diacetoxypalladium (5.61 mg, 0.03 mmol), acetoxysilver (125 mg, 0.75 mmol) and triphenylphosphane (13.11 mg, 0.05 mmol) in toluene (6 mL) under nitrogen in a microwave vial was stirred at 120 °C overnight. The reaction mixture was then filtered through celite and the filtrate was concentrated. Column chromatography of the residue (0-60% ethyl acetate in Heptane) followed by concentration of the appropriate fractions gave the title compound (46.0 mg, 58.2 %): 1H NMR (500 MHz, DMSO) 7.42 - 7.77 (4H, m), 8.07 - 8.17 (4H, m), 8.18 - 8.26 (1H, m), 10.36 (1H, s).

Intermediate 86: 2-(difl uoromethoxy)-4-(l -phenyl- l//-imid:izol-4-yl)benzaldehyde

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.192 g, 0.64 mmol) and 4-bromo-l -phenyl- U/-imidazole (0.115 g, 0.52 mmol, CAS RN 1246555-43-0).

Yellow solid (0.117 g, 72 %): 1H NMR (500 MHz, DMSO) 7.29 - 7.61 (4H, m), 7.73 - 7.77 (2H, m), 7.83 (1H, s), 7.87 - 7.92 (2H, m), 8.46 (1H, d), 8.63 (1H, d), 10.24 (1H, s).

Intermediate 87 : 2-(difluoromethoxy)-4-(2-oxo-3-phenylimidazolidin-l-yl)benzaldehyde

A solution of l-phenylimidazolidin-2-one (81 mg, 0.50 mmol), 4-bromo-2- (difluoromethoxy)benzaldehyde (188 mg, 0.75 mmol), cesium carbonate (326 mg, 1.00 mmol), Tris(dibenzylideneacetone)dipalladium(0) (22.9 mg, 0.03 mmol) and (9,9-dimethyl- 9H-xanthene-4,5-diyl)bis(diphenylphosphane) (14.47 mg, 0.03 mmol) in toluene (1080 pl) was stirred at 100 °C overnight under nitrogen. The reaction mixture was then allowed to cool down to room temperature and filtered through a pad of celite. The filter cake was washed with di chloromethane and the filtrate was concentrated. Column chromatography of the residue (0-60% ethyl acetate in Heptane) gave the title compound (136 mg, 82 %): 1H NMR (500 MHz, DMSO) 4.04 (4H, tq), 7.12 (1H, tt), 7.2 - 7.52 (3H, m), 7.55 (1H, dd), 7.62 - 7.68 (2H, m), 7.82 - 7.9 (2H, m), 10.15 (1H, s).

Intermediate 88: 4-(3-benzyl-2-oxoimidazolidin-l-yl)-2-(difluoromethoxy)benzaldehyde Prepared similar as described for intermediate 87 from l-benzylimidazolidin-2-one (0.088 g,

0.50 mmol, CAS RN 2385-38-8) and 4-bromo-2-(dmuoromethoxy)benzaldehyde (0.188 g, 0.75 mmol). Orange solid (0.131 g, 76 %): 1H NMR (500 MHz, DMSO) 3.39 - 3.47 (2H, m), 3.86 - 3.95 (2H, m), 4.43 (2H, s), 7.17 - 7.49 (7H, m), 7.79 - 7.86 (2H, m), 10.12 (1H, d).

Intermediate 89: 2-(difluoromethoxy)-4-[2-oxo-3-(2-phenylethyl)imidazolidin-l- yl] benzaldehyde

Step . tert-butyl {2-[(2-phenylethyl)amino]ethyl}carbamate

To a mixture of tert-butyl (2-aminoethyl)carbamate (1.583 mL, 10.00 mmol) and triethylamine (1.396 mL, 10.00 mmol) in methanol (20 mL) at 0 °C was added 2- phenylacetaldehyde (1.170 mL, 10 mmol). The resulting reaction mixture was stirred at rt for 2 hours then cooled to 0°C and sodium tetrahydroborate (0.757 g, 20.00 mmol) was added portion wise over 15 minutes. The resulting reaction mixture was allowed to warm up to room temperature and then quenched carefully with IM HC1. The aqueous layer was washed with diethyl ether, then neutralized with sodium hydrogen carbonate (s) and extracted with ethyl acetate twice. The combined ethyl acetate extracts were dried (magnesium sulfate), filtered and concentrated. The residue containing the title compound was used as such directly in the next step.

Step 2'. l-(2-phenylethyl)imidazolidin-2-one tert-butyl {2-[(2-phenylethyl)amino]ethyl}carbamate (2.136 g, 8.08 mmol) was dissolved in THF (25 mL) and potassium tert-butoxide (2.72 g, 24.24 mmol) was added and the resulting reaction mixture is stirred at 60°C for 4 hours. The reaction mixture was allowed to cool to rt, quenched with aq. IM HC1 and concentrated under reduced pressure. The aqueous phase was then extracted with ethyl acetate twice and the combined extracts were dried (magnesium sulfate) filtered and concentrated. Column chromatography of the residue (0-100% ethyl acetate in Heptanes followed by 0-15% MeOH in EtOAc) gave the title compound (0.55 g, 36 %): 1H NMR (500 MHz, CDC13) 2.81 - 2.88 (2H, m), 3.31 - 3.4 (4H, m), 3.43 - 3.49 (2H, m), 7.18 - 7.26 (3H, m), 7.27 - 7.33 (2H, m).

Step 3: 2-(difluoromethoxy)-4-[2-oxo-3-(2-phenylethyl)imidazolidin-l-yl]benzaldehyde (intermediate 89)

Prepared similar as described for intermediate 87 from l-(2-phenylethyl)imidazolidin-2-one (0.095 g, 0.50 mmol) and 4-bromo-2-(difhioromethoxy)benzaldehyde (0.188 g, 0.75 mmol). Orange solid (0.144 g, 80 %): 1H NMR (500 MHz, DMSO) 2.84 (2H, t), 3.43 - 3.54 (4H, m), 3.81 - 3.89 (2H, m), 7.16 - 7.46 (7H, m), 7.76 - 7.85 (2H, m), 10.11 (1H, s).

Intermediate 90: 2-(difluoromethoxy)-4-(2-oxo-3-phenyl-l,3-diazinan-l-yl)benzaldehyde

Prepared similar as described for intermediate 87 from 1 -phenyl- 1, 3 -diazinan-2-one (0.088 g, 0.50 mmol, CAS RN 56535-85-4) and 4-bromo-2-(difluoromethoxy)benzaldehyde (0.188 g, 0.75 mmol). Orange solid (0.139 g, 80 %): 1H NMR (500 MHz, DMSO) 2.15 - 2.25 (2H, m), 3.75 (2H, t), 3.89 (2H, t), 7.19 - 7.47 (8H, m), 7.79 (1H, d), 10.16 (1H, s).

Intermediate 91: 2-(difluoromethoxy)-4-(2-oxo-4-phenylpiperazin-l-yl)benzaldehyde

Prepared similar as described for intermediate 87 from 4-phenylpiperazin-2-one (0.232 g, 1.32 mmol, CAS RN 1445779-80-5) and 4-bromo-2-(difluoromethoxy)benzaldehyde (0.496 g, 1.97 mmol). Orange solid (0.223 g, 49 %, LCMS purity: 66%): 1H NMR (500 MHz, DMSO) 3.62 - 3.67 (2H, m), 3.94 - 3.98 (2H, m), 4.04 (2H, d), 6.83 (1H, ddt), 6.96 - 7.01 (2H, m), 7.24 - 7.31 (2H, m), 7.37 (1H, s), 7.54 (1H, dd), 7.57 (1H, d), 7.89 (1H, d), 10.22 (1H, s).

Intermediate 92: 4-[3-(2,2-difluoroethyl)-2-oxoimidazolidin-l-yl]-2- (difluoromethoxy)benzaldehyde

Step . 7V-(2-chloroethyl)-7V-(2,2-difluoroethyl)urea

To a solution of 2,2-difluoroethan-l -amine (0.352 mL, 5.0 mmol) in dichloromethane (7 mL) at 0°C was added l-chloro-2-isocyanatoethane (0.512 mL, 6.00 mmol) dropwise, then stirred at rt overnight. The reaction mixture was then concentrated to provide the title compound used as such in the next step. White solid (1.1 g): 1H NMR (500 MHz, DMSO) 3.33 (2H, t), 3.36 - 3.45 (2H, m), 3.57 (2H, t), 5.95 (1H, tt), 6.39 (2H, dt).

Step 2'. l-(2,2-difluoroethyl)imidazolidin-2-one

To an ice-cooled suspension of sodium hydride (60% in mineral oil) (0.474 g, 11.84 mmol) in tetrahydrofurane (8 mL) was added a solution of 7V-(2-chloroethyl)-7V-(2,2-difluoroethyl)urea (1.1 g, 5.89 mmol) in tetrahydrofurane (14 mL). The resulting reaction mixture was stirred at rt overnight, then quenched with MeOH and concentrated. The residue was suspended in dichloromethane, washed with aq. IM HC1 and passed through a phase separator. The filtrate was concentrated to obtain the title compound which was used as such in the next step. White solid (0.588 g): 1H NMR (500 MHz, DMSO) 3.22 - 3.28 (2H, m), 3.37 - 3.47 (4H, m), 5.75 (1H, s), 6.09 (1H, tt). Step 3 4-[3-(2,2-difluoroethyl)-2-oxoimidazolidin-l-yl]-2-(difluoromethoxy)benzaldehyde (intermediate 92)

Prepared similar as described for intermediate 87 from l-(2,2-difluoroethyl)imidazolidin-2- one (0.150 g, 1.0 mmol) and 4-bromo-2-(difluoromethoxy)benzaldehyde (0.377 g, 1.50 mmol). Yellow solid (0.227 g, 71 %): 1H NMR (500 MHz, DMSO) 3.61 - 3.64 (2H, m), 3.64 - 3.71 (2H, m), 3.91 - 3.97 (2H, m), 6.23 (1H, tt), 7.16 - 7.49 (2H, m), 7.80 (1H, d), 7.83 (1H, d), 10.12 (1H, s).

Intermediate 93: 2-(difluoromethoxy)-4-[2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-l- yl] benzaldehyde

Step . 7V-(2-chloroethyl)-7V-(2,2,2-trifluoroethyl)urea

To a solution of 2,2, 2-trifluoroethan-l -amine (0.392 mL, 5.0 mmol) in dichloromethane (7 mL) at 0°C was added l-chloro-2-isocyanatoethane (0.512 mL, 6.00 mmol) dropwise, then stirred at rt overnight. The reaction mixture was then filtered and the filter cake was washed with di chloromethane twice and left to dry under high vacuum to yield the title compound used as such in the next step. White solid (0.845 g): 1H NMR (500 MHz, DMSO) 3.33 (2H, t), 3.58 (2H, t), 3.81 (2H, qd), 6.43 (1H, t), 6.68 (1H, t).

Step 2: l-(2,2,2-trifluoroethyl)imidazolidin-2-one

To an ice-cooled suspension of sodium hydride (60% in mineral oil) (332 mg, 8.30 mmol) in tetrahydrofurane (6 mL) is added a solution of 7V-(2-chloroethyl)-7V-(2,2,2-trifluoroethyl)urea (845 mg, 4.13 mmol) in tetrahydrofurane (10 mL). The resulting reaction was stirred at rt overnight, then quenched with methanol and concentrated. The residue was suspended in dichloromethane, washed with aq. IM HC1 and passed through a phase separator. The filtrate was concentrated to afford the title compound used as such in the next step. White solid (0.715 g): 1H NMR (500 MHz, DMSO) 3.27 (2H, dd), 3.42 (2H, dd), 3.81 (2H, q).

Step 3: 2-(difluoromethoxy)-4-[2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-l-yl]benzaldehyde (intermediate 93)

Prepared similar as described for intermediate 87 from l-(2,2,2-trifluoroethyl)imidazolidin-2- one (0.168 g, 1.0 mmol) and 4-bromo-2-(difluoromethoxy)benzaldehyde (0.377 g, 1.50 mmol). Yellow solid (0.225 g, 66 %): 1H NMR (500 MHz, DMSO) 3.66 (2H, dd), 3.94 - 4.01 (2H, m), 4.08 (2H, q), 7.16 - 7.5 (2H, m), 7.80 (1H, d), 7.84 (1H, d), 10.13 (1H, s).

Intermediate 94: 2-(difluoromethoxy)-4-[(57?5)-2-oxo-5-phenyl-l,3-oxazolidin-3- yl] benzaldehyde

Prepared similar as described for intermediate 87 from (57?5)-5-phenyl-l,3-oxazolidin-2-one (0.163 g, 1.0 mmol, CAS RN 7693-77-8) and 4-bromo-2-(difhioromethoxy)benzaldehyde (0.377 g, 1.50 mmol). Orange solid (0.285 g, 86 %): 1H NMR (500 MHz, DMSO) 4.11 (1H, dd), 4.56 (1H, t), 5.82 (1H, t), 7.37 (1H, t), 7.41 - 7.5 (3H, m), 7.52 - 7.56 (2H, m), 7.59 - 7.63 (1H, m), 7.70 (1H, d), 7.89 (1H, d), 10.17 (1H, s).

Intermediate 95: 2-(difluoromethoxy)-4-(3-methyl-2-oxoimidazolidin-l-yl)benzaldehyde

Prepared similar as described for intermediate 87 from l-methylimidazolidin-2-one (0.050 g, 0.5 mmol) and 4-bromo-2-(difluoromethoxy)benzaldehyde (0.188 g, 0.75 mmol). Orange solid (0.093 g, 69 %): 1H NMR (500 MHz, DMSO) 2.80 (3H, s), 3.44 - 3.55 (2H, m), 3.81 - 3.92 (2H, m), 7.14 - 7.48 (2H, m), 7.77 - 7.83 (2H, m), 10.11 (1H, s). Intermediate 96: 2-(difluoromethoxy)-4-(3-oxo-4-phenylpiperazin-l-yl)benzaldehyde

Prepared similar as described for intermediate 87 from l-phenylpiperazin-2-one hydrochloride (0.193 g, 0.91 mmol, CAS RN 94783-18-3) and 2-(difluoromethoxy)-4- iodobenzaldehyde (0.226 g, 0.76 mmol, from intermediate 85, step 3). Orange solid (0.098 g, 37 %). m/z (ES+) [M+H]⁺ = 347.

Intermediate 97: 4-[3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-l-yl]-2-

(difluoromethoxy)benzaldehyde

Step . l-acetyl-3-(4-chl oro-3 -fluorophenyl)imidazolidin-2-one

A solution of l-acetylimidazolidin-2-one (0.641 g, 5 mmol), 4-bromo-l -chi oro-2 - fluorobenzene (1.571 g, 7.50 mmol), cesium carbonate (3.26 g, 10.00 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.229 g, 0.25 mmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (0.145 g, 0.25 mmol) in toluene (10 mL) was stirred at 100 °C overnight under nitrogen. The reaction mixture was then allowed to cool to rt and filtered through a pad of celite. The filter cake was washed with dichloromethane and the filtrates were concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 0-100 %) gave the title compound (1.020 g, 79 %): 1H NMR (500 MHz, DMSO) 2.42 (3H, s), 3.77 - 3.85 (2H, m), 3.85 - 3.91 (2H, m), 7.41 - 7.49 (1H, m), 7.57 - 7.66 (1H, m), 7.74 - 7.81 (1H, m). Step 2'. l-(4-chl oro-3 -fluorophenyl)imidazolidin-2-one

Potassium carbonate (1.648 g, 11.92 mmol) was added to a solution of l-acetyl-3-(4-chl oro-3 - fluorophenyl)imidazolidin-2-one (1.02 g, 3.97 mmol) in methanol (20 ml). The resulting reaction mixture was stirred at room temperature overnight. Water was added and the reaction mixture was filtered and the filter cake washed with water to yield the title compound as a light yellow solid (0.656 g, 77 %): 1H NMR (500 MHz, DMSO) 3.37 - 3.45 (2H, m), 3.8 - 3.87 (2H, m), 7.20 (1H, s), 7.32 (1H, ddd), 7.48 (1H, t), 7.74 (1H, dd).

Step 3: 4-[3-(4-chloro-3-fluorophenyl)-2-oxoimidazolidin-l-yl]-2- (difluoromethoxy)benzaldehyde (intermediate 97)

Prepared similar as described for intermediate 87 from l-(4-chloro-3- fluorophenyl)imidazolidin-2-one (0.215 g, 1.0 mmol) and 4-bromo-2-(difluoromethoxy) benzaldehyde (0.377 g, 1.50 mmol). Yellow solid (0.315 g, 82 %): 1H NMR (500 MHz, DMSO) 3.97 - 4.12 (4H, m), 7.29 (1H, t), 7.49 (1H, ddd), 7.54 - 7.57 (1H, m), 7.60 (1H, t), 7.81 (1H, dd), 7.85 (1H, d), 7.87 (1H, d), 10.15 (1H, s).

Intermediate 98: 2-(difluoromethoxy)-4-[3-(2,4-difluorophenyl)-2-oxoimidazolidin-l- yl] benzaldehyde

Prepared similar as described for intermediate 87 from l-(2,4-difluorophenyl)imidazolidin-2- one (0.198 g, 1.0 mmol, prepared similar as described for intermediate 93, steps 1 and 2, from 2,4-difluoroaniline and l-chloro-2-isocyanatoethane) and 4-bromo-2-(difhroromethoxy) benzaldehyde (0.377 g, 1.50 mmol). Yellow solid (0.301 g, 82 %): 1H NMR (500 MHz, DMSO) 3.95 (2H, dd), 4.10 (2H, dd), 7.15 - 7.21 (1H, m), 7.33 (1H, t), 7.42 (1H, ddd), 7.52 (1H, dd), 7.62 (1H, td), 7.83 (1H, d), 7.86 (1H, d), 10.14 (1H, s). Intermediate 99: 2-(difluoromethoxy)-4-[(41?)-4-methyl-2-oxo-3-phenylimidazolidin-l- yl] benzaldehyde

Step . (57?)-5-methyl-l-phenylimidazolidin-2-one

A mixture of iodobenzene (0.280 mL, 2.50 mmol), (3 R)-3 -aminobutanoic acid (258 mg, 2.5 mmol), copper(I) iodide (95 mg, 0.50 mmol) and potassium phosphate (2.12 g, 10.00 mmol) in DMSO (4 mL) was stirred at 120°C for 2.5 hours. The reaction mixture was then allowed to cool to rt, diluted with ethyl acetate and filtered through celite. The filtrate was washed with aq. sat. sodium hydrogen carbonate and the water layer was extracted twice with ethyl acetate. The water layer was brought to pH 4 and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was dissolved in toluene (20 mL) and tri ethylamine (1.2 mL, 8.60 mmol) then concentrated. The residue was dissolved in toluene (20 mL) and triethylamine (1.2 mL, 8.60 mmol) and diphenyl phosphorazidate (1.616 mL, 7.50 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes and at 100 °C for 1 h. The reaction mixture was then allowed to cool to rt, partitioned between ethyl acetate and aq. sat. sodium hydrogen carbonate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 0-100 %) followed by concentration of the appropriate fractions gave the title compound slightly contaminated with diphenyl phosphate and used as such in the next step. Yellow gum (0.400 g, 91 %): 1H NMR (500 MHz, DMSO) 1.17 (3H, d), 2.94 - 3.02 (1H, m), 3.56 (1H, td), 4.46 (1H, dp), 6.99 - 7.04 (1H, m), 7.13 - 7.17 (1H, m), 7.28 - 7.34 (2H, m), 7.43 - 7.49 (2H, m). Step 2'. 2-(difluoromethoxy)-4-[(4A)-4-methyl-2-oxo-3-phenylimidazolidin-l- yl]benzaldehyde (intermediate 99)

Prepared similar as described for intermediate 87 from (5A)-5-methyl-l-phenylimidazolidin- 2-one (0.176 g, 1.0 mmol) and 4-bromo-2-(difhroromethoxy) benzaldehyde (0.377 g, 1.50 mmol). Yellow oil (0.219 g, 63 %): 1H NMR (500 MHz, DMSO) 1.26 (3H, d), 3.66 (1H, dd), 4.24 (1H, t), 4.6 - 4.71 (1H, m), 7.18 - 7.22 (1H, m), 7.35 (1H, t), 7.4 - 7.45 (2H, m), 7.5 - 7.58 (3H, m), 7.83 (1H, d), 7.86 (1H, d), 10.15 (1H, s).

Intermediate 100: 2-(difluoromethoxy)-4-[(31?₁S)-2-oxo-3-phenylpyrrolidin-l- yl] benzaldehyde

Prepared similar as described for intermediate 87 from (3A5)-3-phenylpyrrolidin-2-one (0.125 g, 0.78 mmol, CAS RN 6836-97-1) and 4-bromo-2-(difluoromethoxy) benzaldehyde (0.292 g, 1.16 mmol). Yellow solid (0.232 g, 90 %): 1H NMR (500 MHz, DMSO) 2.19 - 2.3 (1H, m), 2.54 - 2.64 (1H, m), 3.93 - 4 (1H, m), 4 - 4.07 (2H, m), 7.25 - 7.4 (6H, m), 7.66 (1H, ddd), 7.89 (1H, d), 7.96 (1H, d), 10.18 (1H, s).

Intermediate 101: 2-(difluoromethoxy)-4-[(41?_iy)-3-methyl-2-oxo-4-phenylimidazolidin-l- yl] benzaldehyde

Step . (3A5)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoic acid To a solution of (37?5)-3-amino-3 -phenylpropanoic acid (2.48 g, 15 mmol) in methanol (27 ml) at rt was added triethylamine (4.18 ml, 30.00 mmol) followed by di-tert-butyl dicarbonate (4.91 g, 22.50 mmol). The resulting reaction mixture was stirred at room temperature overnight, then concentrated. The residue was used as such in the next step.

Step 2'. tert-butyl (57?5)-2-oxo-5-phenylimidazolidine-l-carboxylate

To a mixture of (37?5)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoic acid (1.99 g, 7.5 mmol) in toluene (25 ml) was added triethylamine (2.62 ml, 18.75 mmol) followed by diphenyl phosphorazidate (1.94 ml, 9.00 mmol) dropwise. The resulting reaction mixture was stirred at 75°C overnight, then allowed to cool to rt and quenched carefully with aq. sat. sodium hydrogen carbonate. The water layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 0-100%) followed by concentration of the appropriate fractions gave the title compound (0.221 g, 11 %): 1H NMR (500 MHz, DMSO) 1.19 (9H, s), 2.97 (1H, ddd), 3.74 (1H, td), 5.12 (1H, dd), 7.23 - 7.27 (2H, m), 7.27 - 7.33 (1H, m), 7.35 - 7.41 (3H, m).

Step 3: tert-butyl (57?5)-3-[3-(difluoromethoxy)-4-formylphenyl]-2-oxo-5- phenylimidazolidine- 1 -carboxylate

Prepared similar as described for intermediate 87 from tert-butyl 5RS)-2-oxo-5- phenylimidazolidine-1 -carboxylate (0.221 g, 0.84 mmol) and 4-bromo-2-(difluoromethoxy) benzaldehyde (0.317 g, 1.26 mmol). Yellow solid (0.249 g, 68 %): 1H NMR (500 MHz, DMSO) 1.26 (9H, s), 3.73 (1H, dd), 4.39 (1H, t), 5.32 (1H, dd), 7.21 - 7.54 (6H, m), 7.64 (1H, dd), 7.73 (1H, d), 7.86 (1H, d), 10.17 (1H, s). Step 4 2-(difluoromethoxy)-4-[(47?5)-2-oxo-4-phenylimidazolidin-l-yl]benzaldehyde

To a solution of tert-butyl (57?5)-3-[3-(difluoromethoxy)-4-formylphenyl]-2-oxo-5- phenylimidazolidine-1 -carboxylate (249 mg, 0.58 mmol) in 1,4-dioxane (1.0 mL) was added hydrogen chloride in 1,4-dioxane (720 pl, 2.88 mmol) and stirred at room temperature overnight. The reaction mixture was then concentrated and concentrated twice from toluene to afford the title compound used as such in the next step. Yellow solid (0.198 g).

Step 5 2-(difluoromethoxy)-4-[(47?5)-3-methyl-2-oxo-4-phenylimidazolidin-l- yl]benzaldehyde (intermediate 101)

To a mixture of 2-(difluoromethoxy)-4-[(47?5)-2-oxo-4-phenylimidazolidin-l- yl]benzaldehyde (0.198 g, 0.60 mmol) in THF (3.0 mL) at 0°C was added sodium hydride (28.6 mg, 0.72 mmol), then stirred for 30 min at rt. The reaction mixture was then cooled to 0°C and iodomethane (0.045 mL, 0.72 mmol) was added. The resulting reaction mixture was then stirred at rt for 2 h, then carefully quenched with water and extracted into ethyl acetate. The organic layer was dried (magnesium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 0- 100%) followed by concentration of the appropriate fractions gave the title compound as a colorless oil (0.141 g, 68 %): 1H NMR (500 MHz, DMSO) 2.62 (3H, s), 3.67 (1H, dd), 4.29 - 4.38 (1H, m), 4.78 (1H, dd), 7.16 - 7.36 (1H, m), 7.36 - 7.45 (5H, m), 7.56 (1H, dd), 7.75 (1H, d), 7.80 (1H, d), 10.12 (1H, s).

Intermediate 102: 2-(difluoromethoxy)-4-[(45)-4-methyl-2-oxo-3-phenylimidazolidin-l- yl] benzaldehyde Step . (55)-5-methyl-l-phenylimidazolidin-2-one

Prepared similar as described for intermediate 99, step 1, from (3S)-3 -aminobutanoic acid (0.258 g, 2.5 mmol) and iodobenzene (0.28 ml, 2.5 mmol). Off-white solid (0.250 g, 57 %): 1H NMR (500 MHz, DMSO) 1.18 (3H, d), 2.98 (1H, ddd), 3.56 (1H, td), 4.46 (1H, dp), 6.83 (1H, s), 7.01 (1H, tt), 7.28 - 7.33 (2H, m), 7.43 - 7.49 (2H, m).

Step 2: 2-(difluoromethoxy)-4-[(45)-4-methyl-2-oxo-3-phenylimidazolidin-l-yl]benzaldehyde (intermediate 102)

Prepared similar as described for intermediate 87 from (55)-5-m ethyl- 1-phenylimidazolidin- 2-one (0.250 g, 1.42 mmol) and 4-bromo-2-(difhroromethoxy) benzaldehyde (0.534 g, 2.13 mmol). Yellow oil (0.425 g, 86 %): 1H NMR (500 MHz, DMSO) 1.27 (3H, d), 3.68 (1H, dd), 4.26 (1H, t), 4.66 (1H, dp), 7.17 - 7.52 (4H, m), 7.52 - 7.59 (3H, m), 7.84 (1H, d), 7.87 (1H, d), 10.16 (1H, s).

Preparation of Examples 1-140 is described below.

Example 1. 4-{l-[3-chloro-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-l- yl}methyl)phenyl]-LH-l,2,3-triazol-4-yl}-3-methylbenzonitrile

Anhydrous cupric sulfate (55.3 mg, 0.35 mmol) was added to intermediate 2 (75 mg, 0.23 mmol), intermediate 3 (65.2 mg, 0.46 mmol) and L-Ascorbic acid, sodium salt (183 mg, 0.92 mmol) in 1,4-di oxane (0.5 mL) and water (0.500 mL). The resulting mixture was stirred at 40 °C for 4 hours, then filtered and concentrated. Preparative LC-MS (Chromatographic conditions: gradient 10-32% ACN in water (0.2 % formic acid) over 7 min, flow rate 60 mL/min. Column: Xselect CSH C18 OBD 30x150mm) followed by concentration of appropriate fractions gave the title compound as a white solid (37 mg, 34 %): 1H NMR (400 MHz, DMSO-d6, 22°C) 5 0.97 (4H, d), 1.46 (1H, s), 1.70 (3H, d), 1.94 (2H, dt), 2.49 (3H, s), 2.80 (1H, s), 3.02 (1H, d), 3.20 (2H, s), 3.62 (2H, s), 7.65-7.91 (3H, m), 7.95-8.21 (3H, m), 9.26 (1H, s). m/z (ES+) [M+H]⁺ = 466.

Examples 2-3.

The compounds shown below were prepared using procedures analogous to Example 1 using Intermediate 2 and corresponding alkynes. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 4. (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-{4-[4-(trifluoromethyl)phenyl]-lH- l,2,3-triazol-l-yl}phenyl]methyl}piperidin-3-yl]propane-l,2-diol

Anhydrous cupric sulfate (33.6 mg, 0.21 mmol) was added to intermediate 4 (75 mg, 0.21 mmol), l-ethynyl-4-(trifluoromethyl)benzene (46.5 mg, 0.27 mmol) and L- Ascorbic acid, sodium salt (83 mg, 0.42 mmol) in 1,4-dioxane (0.5 mL) and water (0.500 mL). The resulting mixture was stirred at rt for 4 hours, then filtered and concentrated. Preparative LC-MS (Chromatographic conditions: gradient 17-42% ACN in water (0.1 % formic acid) over 7 min, flow rate 60 mL/min. Column: Xselect CSH C18 OBD 30x150mm) followed by concentration of appropriate fractions gave the title compound as a white solid (36 mg, 31 %): 1H NMR (300 MHz, MeOD, 22°C) 5 1.12 (3H, s), 1.35 (1H, d), 1.80 (2H, dd), 1.92-2.16 (2H, m), 2.73 (2H, s), 3.28(1H, s), 3.44 (3H, p), 4.20 (2H, s), 7.17 (1H, t), 7.82 (3H, d), 7.93 (2H, d), 8.17 (2H, d), 9.21 (1H, s). m/z (ES+) [M+H]⁺ = 527.

Examples 5-7.

The compounds shown below were prepared using procedures analogous to Example 1 using Intermediate 4 and corresponding alkynes. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 8. (2S)-2- {(35)- 1- [(2-cyclopropyl-4- {4- [4-(trifluoromethyl)phenyl] -1H- 1 ,2,3- triazol- 1-yl} phenyl)methyl] piperidin-3-yl} propane- 1 ,2-diol

Anhydrous cupric sulfate (31 mg, 0.18 mmol) was added to intermediate 5 (60 mg, 0.18 mmol), l-ethynyl-4-(trifluoromethyl)benzene (31 mg, 0.18 mmol) and L-Ascorbic acid, sodium salt (72 mg, 0.36 mmol) in 1 : 1 1,4-dioxane-water (4 mL). The resulting mixture was stirred at rt for 16 hours, then diluted with ethyl acetate (20 mL) and washed consecutively with water (1 x 20 mL) and brine (1 x 20 mL), then dried (sodium sulfate), filtered and concentrated. Preparative LC-MS of the residue (Chromatographic conditions: gradient 22- 39% ACN in water (0.1 % formic acid) over 7 min, flow rate 60 mL/min. Column: Xselect CSH C18 OBD 30x150mm) followed by concentration of appropriate fractions gave the title compound as a white solid (50 mg, 55 %): 1H NMR (300 MHz, DMSO-d6) 5 0.76 (h, J = 3.5 Hz, 2H), 0.92 (s, 3H), 1.02 (tdd, J = 8.5, 6.0, 3.7 Hz, 3H), 1.45 (d, J = 12.8 Hz, 1H), 1.81 - 1.55 (m, 3H), 2.07 (td, J = 10.4, 9.5, 5.4 Hz, 2H), 2.22 (tt, J = 8.4, 5.3 Hz, 1H), 2.86 (d, J = 10.8 Hz, 1H), 3.13 - 2.96 (m, 1H), 3.78 (s, 2H), 3.19 (s, 2H), 7.42 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 8.2, 2.3 Hz, 1H), 7.83 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.1 Hz, 2H), 9.36 (s, 1H). m/z (ES+) [M+H]⁺ = 501.

Examples 9-14.

The compounds shown below were prepared using procedures analogous to Example 8 using Intermediate 5 and corresponding alkynes. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 15. 4-{4-[3-chloro-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-l- ylj methyl)phenyl|-l//-l .2.3-triazol-l -ylJ-3-methylbenzonitrile

4-azido-3-methylbenzonitrile (51.4 mg, 0.32 mmol, CAS RN 1936558-78-9) was added to a mixture of L-ascorbic acid sodium salt (129 mg, 0.65 mmol), anhydrous cupric sulfate (52 mg, 0.32 mmol) and intermediate 6 (100 mg, 0.32 mmol) in 1 :1 water- 1,4-di oxane (1 mL) and was stirred at rt for 2 hours, then filtered through a pad of celite and concentrated.

The crude product was purified by preparative HPLC (Column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1 % formic acid), Mobile Phase B: acetonitrile; Flow rate: 60 mL/min; Gradient: 10% B to 26% B in 10 min, 26% B; Wave Length: 254/220 nm). Appropriate fractions were concentrated to afford the title compound as a white solid (50.0 mg, 32.2 %): 1H NMR (400 MHz, DMSO, 24°C) 5 0.93 (s, 3H), 1.03 (dt, J = 12.5, 6.9 Hz, 1H), 1.45 (q, J = 12.5 Hz, 1H), 1.68 (t, J = 12.9 Hz, 3H), 1.93 (dt, J = 20.4, 11.0 Hz, 2H), 2.33 (s, 3H), 2.79 (d, J = 10.8 Hz, 1H), 3.01 (d, J = 10.7 Hz, 1H), 3.20 (s, 2H), 3.59 (s, 2H), 3.99 (s, 1H), 4.45 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.91 (dd, J = 8.0, 1.7 Hz, 1H), 7.94-8 (m, 2H), 8.08 (d, J = 1.9 Hz, 1H), 9.14 (s, 1H). m/z (ES+) [M+H]⁺ = 466.

Examples 16-28.

The compounds shown below were prepared using procedures analogous to Example 15 using Intermediate 6 and corresponding alkynes. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 29. (25)-2-[(35')-l-{[2-(difluoromethoxy)-4-{l-[4-(trifluoromethyl)phenyl]-lH- l,2,3-triazol-4-yl}phenyl]methyl}piperidin-3-yl]propane-l,2-diol

L-ascorbic acid sodium salt (93 mg, 0.47 mmol) was added to l-azido-4- (trifluoromethyl)benzene (44.1 mg, 0.24 mmol), intermediate 10 (80 mg, 0.24 mmol) and anhydrous cupric sulfate (38 mg, 0.24 mmol) in 1 :1 1,4-dioxane-water (1 mL). The resulting mixture was stirred at rt for 3 hours, then filtered through filter membrane and concentrated. The crude product was purified by preparative HPLC (Column: Sunfire prep Cl 8 column, 30*150 mm, 5pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 8 min, 40% B; Wave Length: 254/220 nm). Appropriate fractions were concentrated giving the title compound as a yellow solid (59 mg, 46. %): 1H NMR (400 MHz, DMSO, 24°C) 5 0.94 (3H, s), 1.01-1.15 (1H, m), 1.49 (1H, d), 1.68 -1.77 (3H, d), 2.14 (2H, s), 2.92 (1H, d), 3.14 (1H, d), 3.19 (2H, s), 3.74 (2H, s), 4.01- 4.52 (2H, s), 7.29 (1H, t), 7.64 (1H, d), 7.79 (1H, s), 7.86 (1H, dd), 8.05 (2H, d), 8.22 (2H, d), 9.56 (1H, s). m/z (ES+) [M+H]⁺ = 527.

Examples 30-59.

The compounds shown below were prepared using procedures analogous to Example 29 using intermediates 10, 13, 14 and corresponding alkynes. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 60: 4-{4-[3-(difluoromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2- yl]piperidin-l-yl}methyl)phenyl]-lH-pyrazol-l-yl}-3-methylbenzonitrile

To intermediate 21 (156 mg, 0.44 mmol) and intermediate 1 (91 mg, 0.57 mmol) in 2-methyl tetrahydrofuran (3 mL), MeOH (3 mL) and AcOH (0.6 mL) was added (2 -Methylpyridine borane complex (70.8 mg, 0.66 mmol) then stirred overnight at rt. The reaction was then diluted with ethyl acetate (20 mL), washed with aq. IM sodium hydroxide (20 mL). The aqueous layer was extracted with ethyl acetate (1 x 10 mL) and the combined organic layers were washed with brine (1 x 20 mL), dried (magnesium sulfate), filtered and concentrated. The residue was purified by preparative SFC (Chromatographic conditions: MeOH/H2O/NH3 97/3/50mM. Column: Waters BEH 5pm) followed by concentration of the appropriate fractions which gave the title compound (96 mg, 44 %): 1H NMR (600 MHz, DMSO-d6) 0.93 (3H, s), 0.99 (1H, tq), 1.42 (1H, qt), 1.59 - 1.71 (3H, m), 1.85 (2H, dq), 2.41 (3H, s), 2.75 (1H, d), 2.99 (1H, d), 3.17 - 3.24 (2H, m), 3.42 - 3.52 (2H, m), 3.98 (1H, s), 4.46 (1H, t), 7.20 (1H, t), 7.45 (1H, d), 7.53 (1H, s), 7.59 (1H, dd), 7.68 (1H, d), 7.85 (1H, dd), 7.94 (1H, d), 8.31 (1H, s), 8.71 (1H, s). m/z (ES+) [M+H]⁺ = 497.

Examples 61-76.

The compounds shown below were prepared using procedures analogous to Example 60 using intermediate 1 and corresponding aldehyde intermediates. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 77: 2-{3-[3-(difluoromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2- yl]piperidin-l-yl}methyl)phenyl]-lH-pyrazol-l-yl} benzonitrile

Sodium cyanoborohydride (25.9 mg, 0.41 mmol) was added to intermediate 1 (49.3 mg, 0.31 mmol) and intermediate 42 (70 mg, 0.21 mmol) in acetic acid (12.39 mg, 0.21 mmol) and methanol (3mL), then stirred at 50 °C for 16 hours, then concentrated. The crude product was purified by preparative HPLC (Column: Sunfire prep C18 column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 33% B in 10 min, 33% B; Wave Length: 254/220 nm; RTl(min): 9.17). Fractions containing the desired compound were concentrated to afford the title compound as a white solid (50mg, 46 %): 1H NMR (300 MHz, DMSO-d6) 5 0.91 (s, 4H), 1.42 (d, J = 11.8 Hz, 1H), 1.65 (dd, J = 12.2, 6.6 Hz, 3H), 1.91 (q, J = 11.4 Hz, 2H), 2.79 (d, J = 10.8 Hz, 1H), 3.01 (d, J = 10.7 Hz, 1H), 3.18 (d, J = 22.1 Hz, 2H), 3.54 (d, J = 2.4 Hz, 2H), 6.93-7.49 (m, 2H), 7.49-7.64 (m, 2H), 7.72 (d, J = 1.6 Hz, 1H), 7.77 -7.95 (m, 3H), 8.02 (dd, J = 7.7, 1.4 Hz, 1H), 8.16 (s, 1H), 8.52 (d, J = 2.6 Hz, 1H). m/z (ES+) [M+H]⁺ = 483.

Examples 78-86.

The compounds shown below were prepared using procedures analogous to Example 77 using intermediate 1 and corresponding aldehyde intermediates. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 87: (25)-2-[(35)-l-{[2-(cyclopropyloxy)-4-(l-phenyl-lH-pyrazol-3- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

Sodium cyanoborohydride (21 mg, 0.33 mmol) was added to acetic acid (4.7 pl, 0.08 mmol), intermediate 52 (50 mg, 0.16 mmol) and intermediate 1 (52 mg, 0.33 mmol) in methanol (1 mL) at 50 °C. The resulting mixture was stirred at 50 °C for 2 hours, then combined with a parallel batch starting from intermediates 1 and 52 (10 mg each) and concentrated. The crude product was purified by preparative HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13% B to 43% B in 8 min, 43% B; Wave Length: 254; 220 nm; RTl(min): 5.75). Fractions containing the desired compound were concentrated to afford the title compound as a white solid (35.0 mg): 1H NMR (300 MHz, DMSO-d6) 5 0.71 (q, J = 3.3, 2.7 Hz, 2H), 0.77-0.86 (m, 2H), 0.91 (s, 3H), 1.03 (dd, J = 12.1, 8.8 Hz, 1H), 1.35-1.55 (m, 1H), 1.67 (dd, J = 24.6, 11.5 Hz, 3H), 1.83-2.09 (m, 2H), 2.78 (d, J = 11.0 Hz, 1H), 2.92-3.05 (m, 1H), 3.49 (d, J = 29.0 Hz, 2H), 3.99 (tt, J = 6.0, 2.9 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 7.28- 7.42 (m, 2H), 7.44-7.60 (m, 3H), 7.80 (d, J = 1.6 Hz, 1H), 7.86-7.97 (m, 2H), 8.21 (s, 1H), 8.57 (d, J = 2.6 Hz, 1H). m/z (ES+) [M+H]⁺ = 448.

Example 88: (2.S)-2-|(3.S)-l-!|2-cyclopropyl-4-(l-phenyl-l//-pyrazol-3- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

Potassium carbonate (134 mg, 0.97 mmol) was added to intermediate 1 (116 mg, 0.73 mmol) and intermediate 53 (150 mg, 0.49 mmol) in DMF (3 mL) at RT. The resulting mixture was stirred at rt for 16 hours, then filtered through celite and concentrated. The crude product was purified by preparative HPLC (Column: Xselect Peptide CSH C18 19*150mm 5pm, 1; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to 42% B in 7 min, 42% B; Wave Length: 254; 220 nm; RTl(min): 5.53). Fractions containing the desired compound were concentrated to to afford the title compound as a white solid (110 mg, 48 %): 1H NMR (300 MHz, DMSO-d6) 5 0.71 (td, J = 6.0, 4.1 Hz, 2H), 0.86- 1.15 (m, 6H), 1.44 (d, J = 12.6 Hz, 1H), 1.69 (dd, J = 26.0, 12.0 Hz, 3H), 2.01 (q, J = 11.3 Hz, 2H), 2.19 (td, J = 8.4, 4.2 Hz, 1H), 2.84 (d, J = 10.8 Hz, 1H), 3.08 (d, J = 10.7 Hz, 1H), 3.19 (s, 2H), 3.70 (d, J = 28.4 Hz, 2H), 7.03 (d, J = 2.6 Hz, 1H), 7.25-7.41 (m, 2H), 7.43-7.58 (m, 3H), 7.68 (dd, J = 7.8, 1.8 Hz, 1H), 7.83-7.97 (m, 2H), 8.21 (s, 1H), 8.54 (d, J = 2.6 Hz, 1H). m/z (ES+) [M+H]⁺ = 432.

Example 89: (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-(4-methyl-l-phenyl-lH-pyrazol-3- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

Prepared similar as described in example 60 from intermediate 1 (0.088 g, 0.55 mmol) and intermediate 54 (0.14 g, 0.43 mmol) which gave the title compound (0.022 g, 11%): 1H NMR (600 MHz, DMSO) 0.94 (3H, s), 0.95 - 1.05 (1H, m), 1.39 - 1.48 (1H, m), 1.61 - 1.72 (3H, m), 1.82 - 1.92 (2H, m), 2.30 (3H, d), 2.78 (1H, d), 3.02 (1H, s), 3.21 (2H, dt), 3.48 - 3.55 (2H, m), 3.98 (1H, s), 4.45 (1H, t), 7.1 - 7.37 (2H, m), 7.48 - 7.57 (4H, m), 7.65 (1H, dd), 7.84 - 7.89 (2H, m), 8.41 (1H, d). m/z (ES+) [M+H]⁺ = 472.

Example 90: 4-{3-[3-(difluoromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2- yl|piperidin-l-ylj methyl)phenyl|-4-methyl-l //-pyrazol-l-ylj benzonit rile Prepared similar as described in example 60 from intermediate 1 (0.114 g, 0.71 mmol) and intermediate 55 (0.21 g, 0.59 mmol) which gave the title compound (0.083 g, 28 %): 1H NMR (600 MHz, DMSO) 0.95 (3H, s), 1.02 - 1.1 (1H, m), 1.51 (1H, q), 1.69 (2H, d), 1.80 (1H, t), 2.17 (2H, d), 2.30 (3H, s), 2.94 (1H, d), 3.14 - 3.17 (1H, m), 3.23 (2H, d), 3.76 (2H, d), 7.28 (1H, t), 7.58 - 7.64 (2H, m), 7.68 (1H, dd), 7.95 (2H, dd), 8.04 (2H, dd), 8.51 - 8.55 (1H, m). m/z (ES+) [M+H]⁺ = 497.

Example 91: (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-(5-methyl-l-phenyl-lH-pyrazol-3- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

Sodium triacetoxyborohydride (181 mg, 0.85 mmol) was added to intermediate 56 (70 mg, 0.21 mmol) and intermediate 1 (37.3 mg, 0.23 mmol) in di chloroethane (0.5 mL) over a period of 10 minutes. The resulting mixture was stirred at rt for 15 hours, then concentrated. Preparative HPLC (Column: Xselect CSH C18 OBD Column 30* 150mm 5pm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 33% B in 7 min, 33% B; Wave Length: 254; 220 nm; RTl(min): 6.10). Appropriate fractions were concentrated to provide the title compound as a white solid (71 mg, 68 %): 1H NMR (400 MHz, CDC13, 22°C) 5 1.11 (3H, s), 1.41 (1H, s), 1.78 (2H, d), 1.87 (1H, d), 2.09 (1H, s), 2.40 (3H, s), 2.54-2.63 (2H, s), 2.90 (1H, s), 3.31 (1H, s), 3.39 (1H, d), 3.51 (1H, d), 3.78- 4.01 (2H, m), 4.71 (2H, s), 7.4-7.47 (1H, m), 7.5-7.56 (4H, m), 7.59 (1H, d), 7.68 (2H, d). m/z (ES+) [M+H]⁺ = 472.

Examples 92-118

Example 119: (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-(3-phenyl-l,2,4-oxadiazol-5- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

A mixture of intermediate 1 (27.8 mg, 0.17 mmol) in methanol (719 pl) was added to a mixture of intermediate 85 (46 mg, 0.15 mmol) in 2-methyl tetrahydrofuran (719 pl) at room temperature. Acetic acid (144 pl) was then added and the resulting reaction mixture was stirred at room temperature for 1 hour. 2-Methylpyridine borane complex (23.34 mg, 0.22 mmol) was then added and the reaction mixture was stirred at rt over the weekend. The reaction mixture was then concentrated, re-dissolved in ethyl acetate and washed with aq. saturated sodium hydrogen carbonate and brine, then dried (magnesium sulfate), filtered and concentrated. Column chromatography of the residue using methanol in ethyl acetate (stepwise gradient elution, 0-5 %) followed by concentration of the appropriate fractions gave the title compound (18.7 mg, 28 %): 1H NMR (500 MHz, DMSO) 0.93 (3H, s), 0.96 - 1.06 (1H, m), 1.4 - 1.53 (1H, m), 1.6 - 1.77 (3H, m), 1.82 - 1.97 (2H, m), 2.79 (1H, d), 2.95 - 3.03 (1H, m), 3.16 - 3.26 (2H, m), 3.53 - 3.65 (2H, m), 3.97 (1H, s), 4.46 (1H, t), 7.39 (1H, t), 7.59 - 7.68 (3H, m), 7.78 (1H, d), 7.94 (1H, d), 8.05 - 8.16 (3H, m). m/z (ES+) [M+H]⁺ = 460.

Example 120: (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-(l-phenyl-lH-imidazol-4- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

Prepared as described in example 119 from intermediate 1 (0.036 g, 0.23 mmol) and intermediate 86 (0.059 g, 0.19 mmol). Column chromatography of the residue using methanol in ethyl acetate (stepwise gradient elution, 0-15 %) followed by concentration of the appropriate fractions gave the title compound (40 mg, 47 %): 1H NMR (500 MHz, DMSO) 0.92 (3H, s), 0.95 - 1.05 (1H, m), 1.35 - 1.47 (1H, m), 1.57 - 1.72 (3H, m), 1.76 - 1.89 (2H, m), 2.72 - 2.8 (1H, m), 2.93 - 3.01 (1H, m), 3.13 - 3.24 (2H, m), 3.41 - 3.52 (2H, m), 3.95 (1H, s), 4.42 (1H, t), 7.18 (1H, t), 7.39 (1H, dd), 7.44 (1H, d), 7.55 (2H, dd), 7.65 (1H, d), 7.68 - 7.76 (3H, m), 8.36 (2H, s). m/z (ES+) [M+H]⁺ = 458.

Examples 121-137.

The compounds shown below were prepared using procedures analogous to Example 119 using intermediate 1 and corresponding aldehydes. As is appreciated by those skilled in the art, these analogous examples may involve variations in general reaction conditions and isolation methods.

Example 138 : ( 2.S)-2- [(35)- 1- { [2-(difluoromethoxy)-4-(5-phenyl- 1 //-py razol-3- yl)phenyl] methyl} piperidin-3-yl] propane- 1 ,2-diol

Step 1 : 3 ,5-dibromo- 1 - { [2-(trimethylsilyl)ethoxy]methyl } - 1 JT-pyrazole

To a stirred solution of 3,5-dibromo-lH-pyrazole (0.5 g, 2.21 mmol) in tetrahydrofurane (10 mL) at 0 °C was portion wise and carefully added sodium hydride (60% in mineral oil) (0.133 g, 3.32 mmol), then stirred for 30 min. (2-(chloromethoxy)ethyl)trimethylsilane (0.388 g, 2.32 mmol) was then added in one portion, then stirred at rt for 2h. The reaction mixture was then carefully partitioned between ethyl acetate (40 mL) and water (40 mL). The water layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (20 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 10-12 %) followed by concentration of the appropriate fractions gave the title compound as a colorless oil (0.74 g, 94 %): 1H NMR (500 MHz, DMSO) -0.05 (9H, s), 0.78 - 0.86 (2H, m), 3.52 - 3.6 (2H, m), 5.41 (2H, s), 6.77 (1H, s).

Step 2 : 3 -bromo-5 -phenyl- 1 - { [2-(trimethylsilyl)ethoxy ]methyl } - 17/-py razol e

Prepared similar as described for intermediate 57, step 1 from 3,5 -dibromo- 1-{ [2- (trimethylsilyl)ethoxy]methyl}-17/-pyrazole (0.750 g, 2.11 mmol) and phenyl boronic acid (0.257 g, 2.11 mmol). Colorless oil (0.7 g, 1 : 1 mixture of mono and di-arylated products used as such in the next step). Step 3: 2-(difluoromethoxy)-4-(5-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lJ/-pyrazol-3- yl)benzaldehyde

Prepared similar as described for intermediate 57, step 2 from intermediate 19 (0.325 g, 1.09 mmol) and 3-bromo-5-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-17/-pyrazole (0.7 g, mixture from step 2). Colorless syrup (0.22 g, 50 %): 1H NMR (500 MHz, DMSO) -0.07 (9H, s), 0.82 - 0.89 (2H, m), 3.64 - 3.71 (2H, m), 5.51 (2H, s), 7.25 (1H, s), 7.3 - 7.63 (4H, m), 7.67 - 7.72 (2H, m), 7.85 (1H, s), 7.94 (2H, t), 10.27 (1H, s).

Step 4 : (2S)-2- [(35)- 1 - { [2-(difluoromethoxy)-4-(5 -phenyl- 1 - { [2-(trimethyl silyl)ethoxy ]methyl } - U/-pyrazol-3-yl)phenyl]methyl}piperidin-3-yl]propane-l,2-diol

To 2-(difluoromethoxy)-4-(5-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lJ/-pyrazol-3- yl)benzaldehyde (220 mg, 0.49 mmol) and intermediate 1 (0.095 g, 0.59 mmol) in a mixture of 2-methyl tetrahydrofuran (3 mL), MeOH (3 mL) and AcOH (0.6 mL) was added 2- methylpyridine borane complex (79 mg, 0.74 mmol), then stirred overnight. The reaction was then diluted with ethyl acetate (25 mL) and washed with aq. IM sodium hydroxide (25 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layers were washed with brine (10 mL), dried (magnesium sulfate), filtered and concentrated. Column chromatography of the residue using methanol in ethyl acetate (stepwise gradient elution, 0-4 %) followed by concentration of the appropriate fractions gave the title compound (0.17 g, 58 %).

Step 5 (25)-2-[(35)-l-{[2-(difluoromethoxy)-4-(5-phenyl-lJ/-pyrazol-3- yl)phenyl]methyl}piperidin-3-yl]propane-l,2-diol (example 138)

To a solution of ((25)-2-[(35)-l-{[2-(difluoromethoxy)-4-(5-phenyl-l-{[2- (trimethylsilyl)ethoxy]methyl}-U/-pyrazol-3-yl)phenyl]methyl}piperidin-3-yl]propane-l,2-diol (0.17 g, 0.29 mmol) in MeOH (8 mL) was added 1.25 M HC1 in MeOH (10 ml, 12.50 mmol), then stirred at 75 °C for 90 min and concentrated. The residue was purified by preparative HPLC (Chromatographic conditions: gradient 5-95% ACN in 0.1M HCO2H, pH3 - T3 column.

Column: Waters Atlantis T3 ODB 5p 19x150mm) providing the title compound (0.052 g, 39 %): 1H NMR (600 MHz, DMSO) 0.95 (3H, s), 1 - 1.11 (1H, m), 1.50 (1H, q), 1.65 - 1.72 (2H, m), 1.78 (1H, t), 2.15 (2H, dt), 2.94 (1H, d), 3.13 - 3.17 (1H, m), 3.22 (2H, s), 3.74 (2H, t), 7.14 - 7.41 (3H, m), 7.47 (2H, t), 7.57 (1H, d), 7.69 (1H, d), 7.75 (1H, dd), 7.82 - 7.87 (2H, m), 8.23 (2H, d). m/z (ES+) [M+H]⁺ = 458.

Example 139: 4-{4-[3-(difluoromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2- yl]piperidin-l-yl}methyl)phenyl]-LH-imidazol-l-yl}-3-methylbenzonitrile

Step . 4-(4-bromo-U/-imidazol-l-yl)-3 -methylbenzonitrile

A mixture of 4-fluoro-3 -methylbenzonitrile (0.4 g, 2.96 mmol), 4-bromo-l/Z-imidazole (0.479 g, 3.26 mmol) and cesium carbonate (1.447 g, 4.44 mmol) in DMF (5 mL) was stirred at 70°C 2 hours. The reaction mixture was then allowed to cool to rt and partitioned between ethyl acetate (20 mL) and water (20 mL). The water layer was extracted with ethyl acetate (10 mL) and the combined organic layers were washed with water (3 x 10 mL) and brine (10 mL), then dried (sodium sulfate), filtered and concentrated. Column chromatography of the residue using ethyl acetate in heptane (stepwise gradient elution, 20-33 %) followed by concentration of the appropriate fractions gave the title compound (0.48 g, 62 %): 1H NMR (500 MHz, DMSO) 2.25 (3H, s), 7.58 (1H, d), 7.73 (1H, d), 7.86 (1H, dd), 7.96 (1H, d), 7.97 - 8 (1H, m).

Step 2'. 4-{4-[3-(difluoromethoxy)-4-formylphenyl]-U/-imidazol-l-yl}-3-methylbenzonitrile

Prepared similar as described for intermediate 57, step 2, from intermediate 19 (0.12 g, 0.40 mmol) and 4-(4-bromo-U/-imidazol-l-yl)-3-methylbenzonitrile (0.106 g, 0.40 mmol). Yellow solid (0.090 g, 63 %): 1H NMR (500 MHz, DMSO) 2.32 (3H, s), 7.44 (1H, t), 7.65 (1H, d), 7.83 (1H, t), 7.88 (2H, d), 7.90 (1H, dd), 8 - 8.04 (1H, m), 8.14 (1H, d), 8.34 (1H, d), 10.24 (1H, s).

Step 3: 4-{4-[3-(difhroromethoxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2-yl]piperidin-l- yl }methyl)phenyl]- 1/7-imidazol- 1 -yl } -3 -methylbenzonitrile (example 139)

Prepared similar as described for example 60 from intermediate 1 (0.047 g, 0.29 mmol) and 4- {4-[3-(difluoromethoxy)-4-formylphenyl]-lZ7-imidazol-l-yl}-3-methylbenzonitrile (0.080 g, 0.23 mmol) which gave the title compound (0.040 g, 36 %): 1H NMR (600 MHz, DMSO) 0.93 (3H, s), 0.95 - 1.04 (1H, m), 1.36 - 1.47 (1H, m), 1.65 (3H, q), 1.79 - 1.9 (2H, m), 2.32 (3H, s), 2.76 (1H, d), 2.98 (1H, d), 3.16 - 3.23 (2H, m), 3.42 - 3.52 (2H, m), 3.98 (1H, s), 4.45 (1H, t), 7.18 (1H, t), 7.44 (1H, d), 7.63 (1H, d), 7.65 (1H, s), 7.70 (1H, dd), 7.89 (1H, dd), 8.00 (1H, d), 8.04 (1H, d), 8.09 (1H, d). m/z (ES+) [M+H]⁺ = 497.

Example 140: 4-{4-[3-(cyclopropyloxy)-4-({(35)-3-[(25)-l,2-dihydroxypropan-2- yl ] piperidin-l-yl} met hyl)phenyl]-l H-l ,2,3-triazol-l-yl} benzonitrile

Prepared similar as described in example 29 from intermediate 15 ( 0.08 g, 0.24 mmol) and 4- azidobenzonitrile (0.038 mg, 0.27 mmol). White solid (0.069 g, 60 %): 1H NMR (400 MHz, DMSO) 5 0.68-0.82 (2H, m), 0.89 (2H, d), 0.94 (3H, s), 1.10 (1H, d), 1.52 (1H, d), 1.6-1.87 (3H, m), 2.30 (2H, d), 3.00 (1H, s), 3.51 (2H, s), 3.80 (2H, s), 4.01 (1H, dt), 4.58 (1H, s), 7.54 (2H, d), 7.90 (1H, s), 8.09-8.25 (4H, m), 9.50 (1H, s). m/z (ES+) [M+H]⁺ = 474. Example 141. Biological activity of compounds of Examples 1-140 in the TRPV4 calcium mobilisation assay

Assay summary

The assay utilises primary airway smooth muscle cells which endogenously express the human TRPV4 ion channel. Following revival from cryo-vials the cells are plated in microtiter plates and recovered overnight in incubator. Cells are incubated with a calcium dye, subsequently a compound plate is prepared and transferred to the FDSS pCell instrument, where an agonist effect is recorded. After 10 min compound incubation an antagonist effect is measured by challenge with the EC80 concentration of GSK1016790A, a TRPV4 agonist.

Preparation of assay reagents

Assay buffer: HBSS buffer (10X HBSS with Ca2+/Mg2+, HEPES 20 mM, pH 7.4)

Cells: Human Bronchial Smooth Muscle Cells (Lonza, CC-2576, Donor 30996, lot 0000596065) Cell assay medium: DMEM/F-12 no phenol red (Gibco # 21041025), 1% FBS (heat inactivated) Calcium dye: Screen Quest™ Fluo-8 No Wash Calcium Assay Kit (AAT Bioquest #36314)

Step by step protocol for running the assay

1. Day before the experiment: Cryopreserved BSMCs were thawed in cell assay medium and centrifuged for 5 min, 250g. Supernatant was discarded and cell pellet resuspended in cell medium, cells counted with the Nucleocounter (ChemoMetec). Cell concentration was adjusted to 0.25xl0^A6/ml with cell assay medium. Using a Multidrop Combi (Thermofisher) cells were dispensed at 20 pl per well into cell culture 384 well microplates (Greiner #781091), left at room temperature for 20 minutes and then incubated overnight at 37°C, 5% CO2.

2. Day of the experiment: Cells were loaded with 10 pl calcium dye per well and incubated for 45 min at 37°C.

3. Test compounds were prepared in 10 point half-log concentration response starting at 10 mM, 240 nl per well. Compounds were diluted in 60 pl assay buffer per well to achieve a 10 pM top concentration f. c. in the experiment.

4. Agonist challenge compound plate was prepared using GSK1016790A at an EC80 f.c. concentration based on previous results. 5. To generate data on agonism of compounds towards TRPV4 a cell plate and a compound plate were transferred to the FDSS pCell which first reads a baseline for 30 seconds, then adds 10 pl of compounds. Recording of fluorescent kinetic data continues for a total of 3 minutes.

6. For the compound antagonism measurement, after 10 minutes incubation time, the same cell plate and the agonist plate were transferred to the FDSS pCell which again reads a baseline for 30 seconds, then proceeds to add 10 pl of EC80 agonist dilution. Recording of fluorescent kinetic data continues for a total of 3 minutes.

Kinetic data was imported into Genedata Screener Analyzer and the area under curve for each measurement was calculated and normalized to the neutral control (DMSO) and the stimulator control (GSK1016790A) for the agonist measurement or the inhibitor control (l-(((55,7A)-3-(5- cyclopropylpyrazin-2-yl)-7-hydroxy-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-l-JT- benzo[ ]imidazole-6-carbonitrile) for the antagonist measurement.

Table 3 shows the TRPV4 biological activity for the compounds of Examples 1-140 obtained from the TRPV4 calcium mobilisation assay described above with IC50 ranges.

Table 3. TRPV4 Biological activity for compounds of Examples 1-140

IC₅o Ranges: 0.1-10 nM (+++), >10-100 nM (++), >100-1000 nM (+)

For example, the compound of Example 96 was tested according to the TRPV4 calcium mobilisation assay and exhibited an average IC50 value of 0.49 nM (+++).

Table 4 shows the TRPV4 biological activity for reference TRPV4 antagonists in the TRPV4 calcium mobilisation assay described above with IC50 values.

Table 4. TRPV4 Biological Activity for Reference TRPV4 Antagonists.

Those skilled in the art will appreciate that the biological assays described above may be performed using alternative equipment and minor variations to the protocol without significantly affecting the results.

Claims

1. A compound which is a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, wherein: ring A is: a) a 5-membered heteroaryl selected from pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole and tetrazole, wherein ring A is optionally substituted with Ci-3alkyl or C2-4alkoxy alkyl; or b)

R¹ is selected from R^lx, -Ci-3alkylene-R^lx, Ci-3alkyl and Ci-shaloalkyl;

R² is selected from Ci-shaloalkoxy, Ci-3alkoxy, C3-4cycloalkyl, C3-4cycloalkoxy, and halo; R³ is Ci-4 alkyl substituted with one or two occurrences of hydroxyl.

2. The compound of claim 1, which is a compound of Formula (I-A):

Formula (I-A) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹, R² and R³ are as defined in claim 1.

3. The compound of claim 1 or 2, wherein ring A is selected from: wherein R^A is H or Ci-3alkyl; R^Ax is H, Ci-3alkyl or C2-4alkoxy alkyl; R^A1 is H or C1-3 alkyl; R^A2 is C1-3 alkyl; and (R¹) indicates the point of attachment to R¹.

The compound of any of claims 1 to 3, wherein R³ is

5. A compound which is a compound of Formula (II):

R² is selected from Ci-shaloalkoxy, C3-4cycloalkyl and halo.

6. The compound of claim 5, which is a compound of Formula (II- A):

Formula (II- A) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R² are as defined in claim 5.

7. The compound of any preceding claim, wherein ring A is selected from the following moieties: wherein (R¹) indicates the point of attachment to R¹, and wherein R^A is Ci-3alkyl and R^Axis Ci-3alkyl or C2-4alkoxy alkyl.

8. The compound of any of claims 1 to 6, wherein ring

9. The compound of any preceding claim, wherein R¹ is selected from:

10. The compound of any preceding claim, wherein each R^ly is independently selected from fluoro, chloro, -CF3, methyl, nitrile, -OCHF2, -OCH2CF3, - OCH2CHF2 and cyclopropoxy.

11. The compound of any preceding claim, wherein R² is selected from -OCHF2, cyclopropyl and chloro.

12. The compound of any preceding claim, wherein one or more hydrogens present in the compound are deuterated.

13. The compound of any of claims 5 to 12, wherein the compound is a compound of Formula (Il-tZ) or Formula (II-A-t/):

Formula (II-J) Formula (II-A-t/) or a pharmaceutically acceptable salt thereof, wherein ring A, R¹ and R² are as defined in any of claims 5 to 12.

14. A compound which is a compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.

15. The compound of any preceding claim, wherein the compound is a pharmaceutically acceptable salt.

16. A composition comprising the compound of any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

17. A method of inhibiting activity of Transient Receptor Potential Vanilloid 4 (TRPV4), comprising contacting TRPV4 with the compound of any one of claims 1 to 15 or the composition of claim 16.

18. A compound of any of claims 1 to 15 or a composition of claim 16 for use in therapy.

19. A compound of any of claims 1 to 15 or a composition of claim 16 for use in a method of treating or preventing a TRPV4-associated disease or disorder.

20. A method of treating or preventing a TRPV4-associated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 15 or the composition of claim 16 to the subject.

21. Use of the compound of any one of claims 1 to 15 in the manufacture of a medicament for treating or preventing a TRPV4-associated disease or disorder.

22. The compound or composition for use of claim 19, the method of claim 20 or the use of claim 21, wherein the TRPV4-associated disease or disorder is inflammation, a respiratory disease or disorder, a metabolic disease or disorder, a dermatological disease or disorder, a skeletal disease or disorder, a neuromuscular disease disorder, cancer, a genetic disease or disorder, pain, or combination thereof.

23. The compound or composition for use of claim 19, the method of claim 20 or the use of claim 21, wherein the TRPV4-associated disease or disorder is pulmonary edema, systemic edema, hypertension, hyperalgesia, inflammation, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, peripheral neuropathy, asthma, chronic cough, chronic obstructive pulmonary disease (COPD), overactive bladder, incontinence, acoustic cochlear injury, pancreatitis, epilepsy, arthritis, osteoarthritis, multiple sclerosis, stroke, central nervous system (CNS) autoimmune condition, traumatic brain injury, spinal cord injury, brain edema, CNS infection, neuropsychiatric disorder, skeletal degenerative-inflammatory disorder, trigeminal pain, neuropathic pain, chronic vulvar pain, colitis, sclerosis, obesity, diabetes, lung ischemia reperfusion injury, cystic fibrosis, or combination thereof.

24. The compound or composition for use of claim 19, the method of claim 20 or the use of claim 21, wherein the TRPV4-associated disease or disorder is cancer.

25. The compound or composition for use, the method, or the use of claim 24, wherein the cancer is hepatocellular carcinoma, colon cancer, colorectal cancer or non-small cell lung cancer.

26. The compound or composition for use of claim 19, the method of claim 20 or the use of claim 21, wherein the TRPV4-associated disease or disorder is a cardiovascular disease or disorder.

27. The compound or composition for use, the method, or the use of claim 26, wherein the cardiovascular disease or disorder is hypertrophic cardiomyopathy.